Novel steroids

ABSTRACT

Novel 19-nor steroids and 19-nor-D-homo-steroids of the formula ##STR1## wherein R 1  is an organic radical of 1 to 18 carbon atoms containing at least one atom selected from the group consisting of nitrogen, phosphorous and silicon with the atom immediately adjacent to the 11-carbon atom being carbon, R 2  is a hydrocarbon of 1 to 8 carbon atoms, X is selected from the group consisting of a pentagonal ring and a hexagonal ring optionally substituted and optionally containing a double bond, B and C together form a double bond or an epoxy group, the C═A group at position 3 is selected from the group consisting of C═O, ketal, ##STR2## --C═NOH, --C═NOAlK 3  and ═CH 2 , AlK 1 , AlK 2  and AlK 3  are selected from the group consisting of alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts having anti-glucocorticoid activity and a process for their preparation.

STATE OF THE ART

U.S. Pat. No. 4,233,296 describes steroids being substituted in the11-position with substituents other than the present formula whichrequire an organic substituent containing a nitrogen, phosphorous orsilicon atom. U.S. Pat. No. 3,190,796 describes steroids having in ahydroxyl in the 11β-position. Schonemann et al [European Journal ofMedicinal Chemistry, Chimica Therapeutica, Vol. 15, No. 4, (July, Aug.1980), p. 333-335] describes steroids substituted in the 11β-positionwith CH₂ ═, --CH₂ OH and ##STR3##

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel steroids offormula I and their non-toxic, pharmaceutically acceptable acid additionsalts and a novel process and novel intermediates for their preparation.

It is another object of the invention to provide novelantiglucocorticoid compositions and to a novel method of inducingantiglucocorticoidal activity in warm-blooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel steroids of the invention are selected from the groupconsisting of 19-nor steroids and 19-nor-D-homosteroids of the formula##STR4## wherein R₁ is an organic radical of 1 to 18 carbon atomscontaining at least one atom selected from the group consisting ofnitrogen, phosphorous and silicon with the atom immediately adjacent tothe 11-carbon atom being carbon, R₂ is a hydrocarbon of 1 to 8 carbonatoms, X is selected from the group consisting of a pentagonal ring anda hexagonal ring optionally substituted and optionally containing adouble bond, B and C together form a double bond or an epoxy group, theC═A group at position 3 is selected from the group consisting of C═O,ketal, ##STR5## --C═NOH, --C═NOAlK₃ and ═CH₂, AlK₁, AlK₂ and AlK₃ areselected from the group consisting of alkyl of 1 to 8 carbon atoms andaralkyl of 7 to 15 carbon atoms and their non-toxic, pharmaceuticallyacceptable acid addition salts.

Preferably R₂ is a saturated alkyl of 1 to 4 carbon atoms such asmethyl, ethyl, n-propyl or butyl and AlK₁, AlK₂ and AlK₃ are preferablymethyl, ethyl, n-propyl, isopropyl or benzyl. X is preferably anoptionally substituted remainder of a pentagonal ring.

Examples of suitable acids for the non-toxic, pharmaceuticallyacceptable acid addition salts are inorganic acids such as hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acidand organic acids such as acetic acid, formic acid, propionic acid,benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid,citric acid, oxalic acid, glyoxylic acid, aspartic acid, alkane sulfonicacids such as methane sulfonic acid and ethane sulfonic acid, arylsulfonic acids such as benzene sulfonic acid and p-toluene sulfonic acidand arylcarboxylic acid.

A preferred group of compounds are those of the formula ##STR6## whereinR₁, R₂, A and X have the above definitions and their non-toxic,pharmaceutically acceptable acid addition salts.

Preferred compounds of formula I' are those wherein R₂ is methyl, thosewherein X is the remainder of the pentagonal ring ##STR7## wherein R₂has the above definition, the dotted line in the 16,17-position is anoptional double bond, Y is the group ##STR8## n is 1 or 2, R₅ isselected from the group consisting of hydrogen, alkyl of 1 to 8 carbonatoms, alkenyl and alkynyl of 2 to 8 carbon atoms, aryl of 6 to 14carbon atoms and aralkyl of 7 to 15 carbon atoms, R₆ may be the same asR₅ and may be selected from the same group of members as R₅ or --OH, R₃and R₄ are individually selected from the group consisting of hydrogen,--OH, --OAlK₄, --OCOAlK₅, alkenyl and alkynyl of 2 to 8 carbon atoms,##STR9## and --CN wherein AlK₄, AlK₅ and AlK₈ are selected from thegroup consisting of alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15carbon atoms, AlK₆ is selected from the group consisting of optionallysubstituted alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbonatoms and AlK₇ is alkyl of 1 to 8 carbon atoms and R₃ and R₄ form thegroup ##STR10## and Z₁ is selected from the group consisting ofhydrogen, alkyl of 1 to 8 carbon atoms and acyl of an organic carboxylicacid of 1 to 8 carbon atoms and Z₂ is alkyl of 1 to 8 carbon atoms andthose where R₅ is different from R₆.

When R₅ or R₆ are alkyl, they are preferably methyl or ethyl and whenthey are alkenyl or alkynyl, they are vinyl, isopropenyl, allyl, ethynylor propynyl. When R₅ and R₆ are aryl or aralkyl, they are phenyl orbenzyl.

When R₃ or R₄ are OAlK₄ or ##STR11## AlK₄ or AlK₅ are preferably methyl,ethyl, n-propyl, butyl, pentyl, hexyl or benzyl. When R₃ or R₄ arealkenyl or alkynyl, they are preferably vinyl, isopropenyl, allyl or2-methylallyl or ethynyl or --C.tbd.C-AlK₉ where AlK₉ is methyl, ethyl,propyl, isopropyl, isopropenyl, butyl, benzyl or CF₃ --, AlK₆, AlK₇ orAlK₈ have preferably the same values as AlK₄ and AlK₅. The groups R₃ andR₄ are preferably different except where R₃ or R₄ each are hydrogen.

Among the preferred values of ##STR12## wherein Z₁ is hydrogen, alkyl of1 to 8 carbon atoms or acyl of a hydrocarbon of 2 to 8 carbon atoms suchas acetyloxy or benzoyl and Z₂ is alkyl of 1 to 8 carbon atoms such asmethyl.

Other preferred compounds of formula I' are those wherein the D ringdoes not contain any ethylenic unsaturation, R₅ and R₆ are hydrogen, nis 1 and those compounds wherein ═A is ═O as well as those wherein R₁ isa hydrocarbon of 1 to 18 carbon atoms containing a nitrogen atom.

Especially preferred are the compounds of formula I' wherein R₁ is aprimary, secondary or tertiary alkyl of 1 to 8 carbon atoms containingat least one heteroatom of the group consisting of oxygen, nitrogen andsulfur at least one of which is nitrogen or is substituted with anitrogen heterocycle. Examples of alkyl are methyl, ethyl, n-propyl,isopropyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl and cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Examples ofheterocycle containing a nitrogen atom are 3-pyridyl, 4-pyridyl,2-pyridyl, thiazolyl and piperidinyl,

Equally preferred are compounds of formula I' wherein R₁ is aheterocycle containing at least one nitrogen atom optionally substitutedwith alkyl of 1 to 8 carbon atoms.

Other preferred compounds of formula I' are those wherein R₁ is aryl oraralkyl substituted with a group ##STR13## wherein R₇ and R₈ are alkylof 1 to 8 carbon atoms or primary, secondary or tertiary alkyl of 1 to 8carbon atoms containing at least one heteroatoms of the group consistingof nitrogen, sulfur or oxygen of which at least one is nitrogen or aheterocycle containing at least one nitrogen atom. Examples of alkyl arethose mentioned above as preferred and aryl or aralkyl are preferablyphenyl or benzyl and the preferred heterocycles are those mentionedabove. Especially preferred are those wherein R₁ is 2-pyridyl,3-pyridyl, 4-pyridyl, ##STR14## and especially those wherein R₁ is##STR15##

Among other preferred compounds are those wherein R₁ is a nitrogen oxideas well as those wherein B and C form an epoxy. Especially preferredcompounds are those of Examples 1, 3, 4, 8, 10, 11, 12, 14, 16, 17, 20,22, 28 and 29.

The novel process of the invention for the preparation of compounds offormula I' comprises reacting a compound of the formula ##STR16##wherein K is a ketone blocked in the form of a ketal, thioketal, oximeor methyloxime and R₁, R₂ and X have the above definitions with adehydration agent capable of freeing the ketone group to form a compoundof the formula ##STR17## and either reacting the latter with aketalization agent to obtain a compound of the formula ##STR18## orreacting the compound of formula I_(A) ' with NH₂ OH or NH₂ OAlK₃wherein AlK₃ has the above definition to obtain a compound of theformula ##STR19## wherein R is hydrogen or AlK₃ or reacting a compoundof formula I_(A) ' with a reducing agent capable of selectively reducingthe 3-keto group to obtain a compound of the formula ##STR20## andreacting the latter with an etherification agent capable of introducingAlK₁ to obtain a compound of the formula ##STR21## or reacting thecompound of formula I_(D) ' with an esterification agent capable ofintroducing COAlK₂ to obtain a compound of the formula ##STR22## ortransforming the compound of formule I_(A) ' by known methods to acompound wherein C═A is CH₂ and reacting a compound of formula I_(A) ',I_(B) ', I_(C) ', I_(D) ', I_(E) ' or I_(F) ' with an acid to form thecorresponding acid addition salt or with an oxidation agent to obtainwhen R₁ is a radical containing a nitrogen atom a compound having in the11β-position a radical wherein the nitrogen atom is in the oxide formand B and C optionally form an epoxide bridge or when R₁ does notcontain a nitrogen atom, a compound where B and C form an epxoide bridgeand when the compound contains the nitrogen oxide and the B and C groupform an epoxide bridge, selectively reducing the oxidized nitrogen atomin R₁ and optionally reacting the latter with an acid to form the acidaddition salt.

The process of the invention is particularly useful for forming productsof formula I' wherein X form a pentagonal ring of the formula ##STR23##wherein R₂, R₃, R₄, Y and the dotted line in the 16,17-position have theabove definition.

In a preferred mode of the process of the invention, the dehydrationagent capable of freeing the ketone group is a sulfonic acid resin inthe acid form such as a commercial sulfonic acid resin based onpolystyrene or a styrene-divinylbenzene polymer but equally useful areinorganic acids such as sulfuric acid or hydrochloric acid in a loweralkanol or perchloric acid in acetic acid or a sulfonic acid such asp-toluene sulfonic acid.

The ketalization agent is preferably an alcohol or a dialcohol in thepresence of an organic acid such as oxalic acid or p-toluene sulfonicacid. The agent for reducing the ketone group is preferably an alkalimetal hydride as discussed by Walkis [Chemical Society Review, Vol. 5,No. 1 (1976), p. 23]. The etherification agent is preferably an alkylhalide in the presence of a base and the esterification agent ispreferably a carboxylic acid derivative such as the acid anhydride oracid chloride in the presence of a base such as pyridine.

It goes without saying that when one of R₃ or R₄ in the compounds offormula I' obtained above is --OH, the compounds of formula I' may bereacted with an etherification agent or an esterification agent which isone of those discussed above. When R₃ or R₄ is a 17-acyloxy, thecompound may be optionally saponified with a saponification agent suchas a base like sodium hydroxide, potassium hydroxide, potassium amide orpotassium tert.-butylate and the reaction is preferably effected in alower alkanol such as ethanol or methanol but equally useful is lithiumacetylide in ethylenediamine.

The oxidation agent is preferably a peracid such as m-chloroperbenzoicacid, peracetic acid or perphthalic acid or hydrogen peroxide alone orin the presence of hexachloroacetone or hexafluoroacetone. When it isdesired to obtain a compound in which the nitrogen atom of R₁ isoxidized, one uses an equivalent of the oxidation agent and when it isdesired to obtain a compound in which B and C form an epoxide bridge,two equivalents of agent are used. The selective reducing agent for theN-oxide is preferably triphenylphosphine and operating for example withacetic acid.

Another object of the invention is a process for the preparation of thecompounds of formula II wherein a compound of the formula ##STR24## isreacted with a compound selected from the group consisting of LiCu(R₁)₂, LiR₁ and R₁ Mg Hal wherein R₁ has the above definition and Hal ishalogen in the presence of a cuprous halide. In a preferred mode of thesaid process, the reaction is effected at room temperature and thereactant is R₁ Mg Hal in the presence of a cuprous salt.

Another object of the invention is a process for the preparation of acompound of the formula ##STR25## wherein R₁, R₂ and K have the abovedefinitions, R₃ ' is selected from the group consisting of --OH andOR_(c), R_(c) is the residue AlK₄ of an ether group or COAlK₅ of anester group and R₄ ' is hydrogen or alkenyl or alkynyl of 2 to 8 carbonatoms comprising reacting a compound of the formula ##STR26## with acompound selected from the group consisting of LiCu(R₁)₂, R₁ Li and R₁Mg Hal in the presence of a cuprous halide to obtain a compound of theformula ##STR27## and either reducing the latter to obtain thecorresponding 17-ol compound or with an appropriate magnesium to obtainthe corresponding 17α-substituted-17β-ol steroid or with anorganometallic derivative such as a lithium or potassium derivative toobtain the corresponding 17α-substituted-17β-ol steroid or with acyanuration agent to obtain the corresponding 17α-ol-17β-cyano steroid,protecting the hydroxy group and reacting the latter with anorganometallic compound as discussed above to obtain the corresponding17α-substituted-17β-ol steroid and in the case of one of the compoundsobtained is 17-hydroxylated, reacting it with an etherification agent oresterification agent and in the case when one of the compounds containsa 17 substituent with a triple bond, reacting the latter with a reducingagent to obtain the corresponding ethylenic derivative.

In a preferred mode of the latter process, the reaction of the compoundof formula IV with a compound of the group consisting of R₁ Li,LiCu(R₁)₂ or R₁ Mg Hal is effected under the previously describedconditions. The different reactants for reaction with the compounds offormula V are known in steroid chemistry and are illustrated in thespecific examples.

The novel intermediates of the invention are the compounds of formula IIand V. Particularly preferred compounds of the invention are3,3-[1,2-ethanediylbisoxy]-11β-[4-trimethylsilyl-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol,3,3-[1,2-ethanediyl-bisoxy]-11β-(4-pyridyl)-17α-(prop-1-ynyl)-.DELTA.⁹-estrene-5α,17β-diol,3,3-[1,2-ethanediyl-bisoxy]-11β-[3-(N,N-dimethylamino)-propyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol,3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol,3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N,-dimethylaminoethoxy)phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol,3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17Δ-Δ⁹-pregnene-20-yne-5α,17β-diol and3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-2-ynyl)-Δ⁹ -estrene-5α,17β-diol.

The cmpounds of formula III are especially of formula IV used to preparethe compounds of formula II or V are generally known compounds which canbe prepared by reacting the corresponding Δ⁵(10),9(11) steroids with anepoxidation agent selective for the 5(10) double bond, for example withhydrogen peroxide in the presence of hexachloroacetone orhexafluoroacetone as described in French Pat. No. 2,423,486. The newcompound,3,3-[1,2-ethanediyl-bisoxy]-17α-(prop-1-ynyl)-5α,10α-epoxy-Δ⁹(11)-estrene-17β-ol is prepared in the Examples

The starting compounds of formula II are described in lines 11 to 21 ofcolumn 4 of U.S. Pat. No. 4,147,695.

The following compounds are compounds falling within the scope of theinvention:

(A) compounds of the formula ##STR28## wherein the A, R₁, R₂, R₃ and R₄substitutes are indicated in Table I.

    __________________________________________________________________________    A      R.sub.1            R.sub.2                                                                            R.sub.3  R.sub.4                               __________________________________________________________________________            ##STR29##         CH.sub.3                                                                           OH       CCH                                   "      "                  "    "        CCCF.sub.3                            "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CCSiMe.sub.3                          "      "                  "    CCH      OH                                    "      "                  "    CCSiMe.sub.3                                                                           "                                     "      "                  CH.sub.2 CH.sub.3                                                                  OH       CCH                                   "      "                  "    OH       CCCH.sub.3                            "      "                  "    OH       CH.sub.2CCH                           "      "                  CH.sub.3                                                                            ##STR30##                                                                             H                                     "      "                  "    "        OH                                    HON(E) "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    CCH      OH                                    "      "                  "    OH       CH.sub.2CCH                           HON(Z) "                  "    "        CCH                                   "      "                  "    "         CCCH.sub.3                           "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    O                                                                                     ##STR31##         "    OH       CCH                                   "      "                  "    "        CCCF.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CCCl                                  "      "                  "    "        C CSiMe.sub.3                         "      "                  "    CCH      OH                                    "      "                  "    CCSiMe.sub.3                                                                           "                                     "      "                  CH.sub.2 CH.sub.3                                                                  OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  CH.sub.3                                                                            ##STR32##                                                                             H                                     "      "                  "    "        OH                                    "      "                  "                                                                                   ##STR33##                                                                             H                                     HON(E) "                  "    OH       CCH                                   "      "                  "    "        C CCH.sub.3-" " " " CCCH.sub.2                                                CH.sub.3                              "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR34##                                                                             H                                     HON(Z) "                  "    "        "                                     "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CH.sub.2CCH                           "      "                  "    C CH     OH                                    O                                                                                     ##STR35##         "    "        "                                     "      "                  "    OH       CCH                                   "      "                  "    "        CCCF.sub.3                            "      "                  "    "        CCCl                                  "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CCSiMe.sub.3                          "      "                  "                                                                                   ##STR36##                                                                             H                                     HON(E) "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    HON(Z) "                  "    "        "                                     "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           O                                                                                     ##STR37##         "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CCCF.sub.3                            "      "                  "    CCSiMe.sub.3                                                                           OH                                    "      "                  "                                                                                   ##STR38##                                                                             H                                     "      "                  "    "        OH                                    "      "                  "                                                                                   ##STR39##                                                                             H                                     "      "                  CH.sub.2 CH.sub.3                                                                  OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCl                                  "      "                  "    "        CCCH.sub.2CH.sub.3                    "      "                  "    "        CCSiMe.sub. 3                         "      "                  "    "        CH.sub.2CCH                           "      "                  "                                                                                   ##STR40##                                                                             H                                     HON(E) "                  CH.sub.3                                                                           CCH      OH                                    "      "                  "                                                                                   ##STR41##                                                                             H                                     "      "                  "    OH       CH.sub.2CCH                           HON(Z) "                  "    "        "                                     "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR42##                                                                             H                                     O                                                                                     ##STR43##         "    "        "                                     "      "                  "    C CH     OH                                    "      "                  "    OH       CH.sub.2CCH                           "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CCCF.sub.3                            "      "                  "    "        CCH                                   "      "                  "    "        CCSiMe.sub.3                          HON(E) "                  "    "        CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CCCl                                  "      "                  "    "        CCSiMe.sub.3                          "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    HON(Z) "                  "    "        "                                     "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCH.sub.2CH.sub.3                    "      "                  "    "        CCCl                                  "      "                  "    "        CCSiMe.sub.3                          "      "                  "    "        CH.sub.2CCH                           O                                                                                     ##STR44##         "    "        CCH                                   "      "                  "    "        CCCF.sub.3                            "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCl                                  "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        H                                     "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR45##                                                                             H                                     "                                                                                     ##STR46##         "    "        "                                     "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCl                                  "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "                                                                                     ##STR47##         "    "        "                                     "      "                  "    OH       CCH                                   "      "                  "    "         CCCF.sub.3                           "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        H                                     "                                                                                     ##STR48##         "    "        CCH                                   "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR49##                                                                             H                                     "                                                                                     ##STR50##         "    "        "                                     "      "                  "    CCH      OH                                    "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "                                                                                     ##STR51##         "    "        CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH-" " " CCH OH              "      "                  "                                                                                   ##STR52##                                                                             H                                     "                                                                                     ##STR53##         "    "        "                                     "      "                  "    CCH      OH                                    "      "                  "    OH       CCCF.sub.3                            "      "                  "    "        CCH                                   "      "                  "    "        CH.sub.2CHCH.sub.2                    "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CH.sub.2                              "      "                  "                                                                                   ##STR54##                                                                             CH.sub.3                              "      "                  "    OH       CH.sub.2CN                            HON(E) "                  "    "        CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CCCl                                  "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR55##                                                                             H                                     HON(Z) "                  "    "        "                                     "      "                  "    CCH      OH                                    "      "                  "    OH       CCH                                   "      "                  "    "        C CCH.sub.3                           "      "                  "    "        CCCH.sub.2CH.sub.3                    "      "                  "    "        CCCl                                  "      "                  "    "        CH.sub.2CCH                           O      "                  CH.sub.2 CH.sub.3                                                                  "        CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CH.sub.2CHCH.sub.2                    "      "                  "                                                                                   ##STR56##                                                                             CH.sub.3                              "      "                  "                                                                                   ##STR57##                                                                             H                                     "      "                  "    C CH     OH                                    "                                                                                     ##STR58##         CH.sub.3                                                                           OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCl                                  "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CH.sub.2CHCH.sub.2                    "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR59##                                                                             H                                     "      "                  "                                                                                   ##STR60##                                                                             CH.sub.3                              "      "                  "                                                                                   ##STR61##                                                                             H                                     "                                                                                     ##STR62##         "    "        "                                     "      "                  "    "        CH.sub.3                              "      "                  "                                                                                   ##STR63##                                                                             H                                     "      "                  "    CCH      OH                                    "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCl                                  "      "                  "    "        CCCH.sub.2 CH.sub. 3                  "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CH.sub.2CHCH.sub.2                    "                                                                                     ##STR64##         "    "        CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR65##                                                                             H                                     "                                                                                     ##STR66##         "    OH       C CH                                  "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR67##                                                                             H                                     "                                                                                     ##STR68##         "    OH       CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "                                                                                     ##STR69##         "    "        CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCl                                  "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR70##                                                                             H                                     "                                                                                     ##STR71##         "    "        "                                     "      "                  "    CCH      OH                                    "      "                  "    OH       CCH                                   "      "                  "    "        C CCH.sub.3                           "      "                  "    "        CCCl                                  "      "                  "    "        CH.sub.2CCH                           "      Me.sub.3 SiCH.sub.2                                                                              "    "        CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    HON(E) "                  "    "        "                                     "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "         CH.sub.2CCH                          HON(Z) "                  "    CCH      OH                                    "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           O                                                                                     ##STR72##         "    "        CCCH.sub.3                            "      "                  "                                                                                   ##STR73##                                                                             H                                     "                                                                                     ##STR74##         "    "        "                                     "      "                  "    OH       C CH                                  "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CH.sub.2CHCH.sub.2                    "      "                  "    "        CH.sub.2 CN                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR75##                                                                             H                                     "      "                  "                                                                                   ##STR76##                                                                             CH.sub.3                              "      "                  "    OH       H                                     "                                                                                     ##STR77##         "    "        CCH                                   "      "                  "    "        C CCF.sub.3                           "      "                  "    "        CCCH.sub.2 CH.sub.3                   "      "                  "    "        CCCl                                  "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR78##                                                                             H                                     "      "                  "                                                                                   ##STR79##                                                                             CH.sub.3                              "      "                  CH.sub.2 CH.sub.3                                                                  OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2C CH                          "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR80##                                                                             H                                     "                                                                                     ##STR81##         CH.sub.3                                                                           OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR82##                                                                             H                                     "                                                                                     ##STR83##         "    "        "                                     "      "                  "    CCH      OH                                    "      "                  "    OH       CCH                                   "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CH.sub.2CHCH.sub.2                    "      "                  "    "        CH.sub.2 CN                           "                                                                                     ##STR84##         "    "        CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        CH.sub.2CHCH.sub.2                    "      "                  "    "        CH.sub.2CN                            "      "                  "    CCH      OH                                    "                                                                                     ##STR85##         "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "                                                                                   ##STR86##                                                                             H                                     "                                                                                     ##STR87##         "    "        "                                     "      "                  "    C CH     OH                                    "      "                  "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    "        H                                     "      "                  "    "        CH.sub.3                              "                                                                                     ##STR88##         "    "        CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCF.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "                                                                                     ##STR89##         "    OH       CCH                                   "      "                  "    "        CCCH.sub.3                            "      "                  "    "        CCCF.sub.3                            "      "                  "    "        CH.sub.2CCH                           "      "                  "    CCH      OH                                    "      "                  "    CCCH.sub.3                                                                             "                                     __________________________________________________________________________

(B) compounds of the formula ##STR90## wherein R₁, R₂, R₃ and R₄ havethe definitions in Table II

    __________________________________________________________________________    R.sub.1     R.sub.2                                                                           R.sub.3   R.sub.4                                             __________________________________________________________________________     ##STR91##  CH.sub.3                                                                          OH        CCH                                                 "           "   "         CCCH.sub.3                                          "           "   "         CCCF.sub.3                                          "           "   "         CH.sub.2 CH.sub.3                                   "           "   "         CH.sub.2CCH                                         "           "   CCH       OH                                                   ##STR92##  "   OH        CCH                                                 "           "   "         C CCH.sub.3                                         "           "   "         CCCF.sub.3                                          "           "   "         CCCH.sub.2 CH.sub.3                                 "           "   "         CH.sub.2CCH                                         "           "   "         H                                                   "           "   "         CH.sub.2 CH.sub.3                                   "           "   CCH       OH                                                  "           "                                                                                  ##STR93##                                                                              H                                                   "           "                                                                                  ##STR94##                                                                              CH.sub.3                                             ##STR95##  "   "         "                                                   "           "   OH        CCH                                                 "           "   "         C CCH.sub.3                                         "           "   "         CCCF.sub.3                                          "           "   "         CH.sub.2 CH.sub.3                                   "           "   "         CH.sub.2CCH                                         "           "   CCH       OH                                                  "           "   OH        H                                                    ##STR96##  "                                                                                  ##STR97##                                                                              CH.sub.3                                            "           "   OH        CCH                                                 "           "   "         CCCH.sub.3                                          "           "   "         CCCF.sub.3                                          "           "   "         CH.sub.2 CH.sub.3                                   "           "   "         CH.sub.2C CH                                         ##STR98##  "   "         CCH                                                 "           "   "         CCCH.sub.3                                          "           "   "         CCCF.sub.3                                          "           "   "         CH.sub.2CH.sub.3                                    "           "   "         CH.sub.2CCH                                         "           "   "         H                                                   "           "   "         CH.sub.3                                            "           "   CCH       OH                                                  __________________________________________________________________________

Also prepared are the epoxides of the compounds of Table II.

The antiglucocorticoid compositions of the invention are comprised of anantiglucocorticoidally effective amount of at least one compound offormula I' and its non-toxic-pharmaceutically acceptable acid additionsalts and an inert pharmaceutical carrier or excipient. The compositionsmay be in the form of tablets, dragees, gelules, granules,suppositories, injectable solutions or suspensions, pomades cremes andgels.

Examples of suitable excipients are talc, arabic gum, lactose, starch,magnesium stearate, cacao butter, aqueous or non-aqueous vehicles, fattybodies of animal or vegetable origin, paraffinic derivatives, glycols,diverse wetting agents, dispersants or emulsifiers and preservatives.

The compositions of the invention have remarkable antiglucocorticoidproperties as can be seen from the pharmalogical data infra. The studyof the products against hormonal receptors shows that the compositionspossess progestomimetic activity or anti-progestomimetic, androgenic orantiandrogenic activity.

The compositions are used principally against secondary effects ofglucocorticoids and are equally useful against troubles due to ahypersecretion of glucocorticoids and especially against aging ingeneral and are particularly active against hypertension,atherosclerosis, osteoporosis, diabetes, obesity as well as depressionof immunity and insomnia. The compositions of the invention also possessantiprogestomimetic activity and are useful for the preparation oforiginal contraceptives and are equally useful against hormonalirregularities.

Some of the compounds of formula I' and their acid addition salts alsopossess progestomimetic activity and are useful for the treatment ofamenorrhea, dysmenorrhea and luteal insufficiencies.

The compositions of the invention also present antiandrogenic activitymaking them useful for the treatment of hypertrophia, hyperandrogenia,anemia, hirsutism and acne.

The novel method of the invention of inducing antigluococorticoidactivity in warm-blooded animals, including humans, comprisesadministering to warm-blooded animals an antiglucocorticoidallyeffective amount of at least one compound of formula I' and theirnon-toxic, pharmaceutically acceptable acid addition salts. The usualdaily dose is 0,15 to 15 mg/kg depending on the specific condition beingtreated and the compound used and the method of administration. Theactive compound may be administered orally, rectally, parenterally orlocally.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it is to be understoodthat the invention is not intended to be limited to the specificembodiments.

EXAMPLE 1 11β-(4-pyridyl)-17α-(prop-1-ynyl-Δ⁴,9 -estradiene-17β-ol-3-one

STEP A: 3,3-[1,2-ethanediyl-bisoxy]-17α-(prop-1-ynyl)-Δ⁵(10), ⁹(11)-estradiene-17β-ol

207 ml of a solution of 1.15% ethyl magnesium bromide in tetrahydrofuranwere stirred at 0° C. while bubbling gaseous propyne dried over calciumchloride therethrough for 90 minutes and the temperature was thenallowed to return to room temperature. The mixture was stirred for onehour while the bubbling was continued. Then a solution of 30 g of3,3-[1,2-ethanediyl-bisoxy]-Δ⁵(10), ⁹(11) -estradiene-17-one in 120 mlof anhydrous tetrahydrofuran and one drop of triethylamine was added tothe mixture over 30 minutes and the mixture was stirred for 2 hours atroom temperature and was then poured into a mixture of ice, distilledwater and ammonium chloride. The stirred mixture was extracted 3 timeswith ether and the organic phase was washed with water, dried andevaporated to dryness under reduced pressure. The residue was driedunder reduced pressure to obtain 35.25 g of3,3-[1,2-ethanediyl-bisoxy]-17α-(prop-1-ynyl)-Δ⁵(10), ⁹(11)-estradiene-17β-ol.

NMR Spectrum (deuterochloroform): Peaks at 0.83 ppm (hydrogens of18-methyl); at 1.85 ppm (hydrogens of methyl of C.tbd.C--CH₃); at 5.65ppm (hydrogens of 11-carbon); at 4 ppm (hydrogens of ethylene ketal).

STEP B:3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol

A mixture of 30 g of the product of Step A in 150 ml of methylenechloride was stirred while bubbling nitrogen therethrough and aftercooling the mixture to 0° C., 1.8 ml of hexafluoroacetone sesquihydratewere added all at once. The mixture was stirred while 4.35 ml of 85%oxygenated water were added and the mixture was stirred at 0° C. for 72hours while continuing to bubble nitrogen therethrough. The solution waspoured into a mixture of 250 g of ice and 500 ml of 0.2 N sodiumthiosulfate solution and the mixture was stirred for a few moments andwas then extracted with methylene chloride. The organic phase was washedwith distilled water, dried over sodium sulfate in the presence ofpyridine and evaporated to dryness under reduced pressure. The residuewas dried under reduced pressure and the 31.6 g of residue werechromatographed over silica gel. Elution with a 9-1 benzeneethyl acetatemixture yield 3,3-[1,2-ethanediyl-bisoxy]-5α10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11) -estrene-17β-ol.

NMR Spectrum (deuterochloroform): Peaks at 0.82 ppm (hydrogens of18-CH₃); at 1.83 ppm (hydrogens of methyl of C.tbd.C--CH₃); at 6.1 ppm(hydrogens of 11-carbon); at 3.92 ppm (hydrogens of ethylene ketal).

STEP C:3,3-[1,2-ethanediyl-bisoxy]-11β-(4-pyridyl)-17α-(prop-1-ynyl)-.DELTA.⁹-estrene-5α,17β-diol

100 ml of a tetrahydrofuran solution of 0.5 to 0.6 M 4-chloropyridylmagnesium bromide prepared from 15 g of 4-chloro-pyridine and 6 g ofmagnesium was added at 20° C. to a solution of 6.16 g of dimethylsulfide-cuprous bromide complex in 40 ml of tetrahydrofuran and themixture was stirred under an inert atmosphere at room temperature for 20minutes. Then, a solution containing 3.7 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol was added thereto over 10 minutes and the mixture wasstirred at room temperature for one hour and was then poured into amixture of cold water and ammonium chloride. The mixture was stirred atroom temperature for 30 minutes and was extracted with ether. Theorganic phase was washed with an aqueous saturated sodium chloridesolution, was dried and evaporated to dryness under reduced pressure.The 6 g of residue were chromatographed over silica gel and eluted witha 1-1 methylene chloride-acetone mixture containing 1 ppm oftriethylamine to obtain 3.15 g of3,3-[1,2-ethanediyl-bisoxy]-11β-(4-pyridyl)-17α-(prop-1-ynyl)-.DELTA.⁹-estrene-5α,17β-diol which was dried towards 60° C. at 0.1 mm Hg whichhad a specific rotation of [α]_(D) ²⁰ =-52°±1.5° (c= 1% in chloroform).

STEP D: 11β-(4-pyridyl)-17α-(prop-1-ynyl)-Δ⁴,9 -estradiene-17β-ol-3-one

A solution of 2.9 g of the product of Step C, 14 ml of methanol and 7 mlof 2 N hydrochloric acid was stirred under an inert atmosphere at roomtemperature for 3 hours and was then admixed with a solution of 200 mlof ether and 90 ml of aqueous saturated sodium bicarbonate solution. Themixture was stirred at room temperature for 15 minutes and the decantedaqueous phase was extracted with ether. The organic phase was washedwith aqueous saturated sodium chloride solution, dried and evaporated todryness under reduced pressure. The 2.3 g of residue werechromatographed over silica gel and eluted with a 6-4 methylenechloride-acetone mixture. The 1.7 g of product was dried for 24 hours at0.1 mm Hg and for 8 hours at 80° C. to obtain11β-(4-pyridyl)-17α-(prop-1-ynyl)-Δ⁴,9 -estradiene-17β-ol-3-one with aspecific rotation of [α]_(D) ²⁰ =+30.5°±1° (c=1% in chloroform).

Using the same procedure, 11β-(3-pyridyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰ =+14°(c=1% in chloroform) and 11β-(2-pyridyl)-17α-(prop-1-yny)-Δ⁴,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰ =-2°(c=1% in chloroform) were prepared.

EXAMPLE 2 11β-[3-(N,N-dimethylamino)-propyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[3-(N,N-dimethylamino)-propyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

12.33 g of dimethyl sulfide-cuprous bromide complex were added over 5minutes at 0° C. to a solution of 0.85 M of 3-(N,N-dimethylamino)-propylmagnesium chloride [prepared from 42 g of chloro3-(N,N-dimethylamino)-propane and 10.5 g of magnesium] and the mixturewas stirred at 0° C. for 25 minutes. A solution of 3.70 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol in 50 ml of tetrahydrofuran was added to the mixturedropwise and the mixture was then stirred at 0° C. for 3 hours and waspoured into a mixture of 40 g of ammonium chloride and 200 ml of icedwater. The mixture was stirred at room temperature for 15 minutes andwas then extracted with ether. The organic phase was washed with aqueoussaturated sodium chloride solution, dried and evaporated to drynessunder reduced pressure. The 4.6 g of residue were chromatographed oversilica gel and eluted with an 8-2 methylene chloride-methanol mixture toobtain 2.55 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[3-(N,N-dimethylamino)-propyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol with a specific rotation of [α]_(D) ²⁰ =-86°±1.5(c=1% in chloroform).

STEP B: 11β-[3-(N,N-dimethylamino)-propyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

A mixture of 2.4 g of the product of Step A, 14 ml of methanol and 7 mlof 2 N hydrochloric acid was stirred under an inert atmosphere at roomtemperature for 4 hours and then 200 ml of isopropyl ether and 90 ml ofaqueous saturated sodium bicarbonate solution were added thereto. Themixture was stirred at room temperature for 30 minutes and the decantedaqueous phase was extracted with ether. The organic extract was washedwith aqueous saturated sodium chloride solution, was dried andevaporated to dryness under reduced pressure. The 1.8 g of residue werechromatographed over silica gel and eluted with an 8-2chloroform-methanol mixture. The 1.30 g of product were dried at 30° to40° C. at 0.1 mm Hg to obtain 1.25 g of11β-[3-(N,N-dimethylamino)-propyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰ =-114°±2.5° (c=1% in chloroform).

EXAMPLE 311β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one

STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A solution of 24 g of 4-(N,N-dimethylaminoethoxy)bromobenzene was addeddropwise over 45 minutes to 90 ml of anhydrous tetrahydrofuran and 2 mlof 1,2-dibromoethane were added as catalyst. After the addition, themixture was stirred at 25° C. for one hour to obtain a solution of 0.7 Mof 4-(N,N-dimethylaminoethoxy)-bromobenzene magnesium which was thenadded to a solution of 6.16 g of dimethylsulfide-cuprous bromide complexin 20 ml of tetrahydrofuran. The mixture was stirred at room temperaturefor 20 minutes and a solution of 3.7 g of3,3-[1,2-(ethanediyl-bisoxy)]-5α,10α-epoxy-17α-prop-1-ynyl-Δ⁹(11)-estrene-17β-ol in 50 ml of tetrahydrofuran was added thereto dropwiseover a few minutes. The mixture was stirred under an inert atmospherefor one hour and was then poured into a solution of 15 g of ammoniumchloride in 20 ml of iced water. The mixture was extracted with etherand the organic phase was washed with aqueous saturated sodium chloridesolution, was dried and evaporated to dryness under reduced pressure.The 18.3 g of oil were chromatographed over silica gel and eluted withchloroform to obtain 4.5 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol with a specific rotation of [α]_(D) ²⁰ =-44°±1.5°(c=1% in chloroform).

STEP B:11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one

9.5 ml of 2 N hydrochloric acid were added to a solution of 4.5 g of theproduct of Step A in 20 ml of methanol and the solution was stirred atroom temperature for 2 hours. 260 ml of ether and 110 ml of an aqueoussaturated sodium bicarbonate solution were added to the mixture whichwas stirred at room temperature for 15 minutes. The decanted aqueousphase was extracted with ether and the organic phase was dried andevaporated to dryness under reduced pressure. The 3.3 g of residue werechromatographed over silica gel and eluted with a 92.5-7.5 methylenechloride-methanol mixture to obtain 1.8 g of amorphous11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰ =+71°(c=1% in chloroform).

EXAMPLE 4 11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A solution of 38 mmoles of p-dimethylaminophenyl magnesium bromide intetrahydrofuran was added to a suspension of 4.1 g of a cuprousbromide-dimethylsulfide complex in 20 ml of tetrahydrofuran and then asolution of 2.45 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol in tetrahydrofuran was added thereto. The mixture wasstirred for 10 minutes and was then hydrolyzed with 50 ml of aqueoussaturated ammonium chloride solution. The decanted aqueous phase wasextracted with ether and the organic phase was washed with water, driedand evaporated to dryness under reduced pressure. The 11 g of residuewere chromatographed over silica gel and eluted with a 6-4cyclohexane-ethyl acetate mixture to obtain 1.8 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol which after crystallization from isopropyl etherand ethyl acetate had a specific rotation of [α]_(D) ²⁰ =- 66.5° (c=1%in chloroform) and a melting point of 210° C. and 750 mg of thecorresponding 11α-compound.

STEP B: 11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

2 ml of concentrated hydrochloric acid were added to a solution of 1.53g of the product of Step A in 60 ml of methanol and after stirring themixture for 30 minutes at room temperature, 150 ml of ether and then 50ml of aqueous N sodium hydroxide solution were added thereto. Thereaction mixture was stirred for 15 minutes and the decanted organicphase was dried and evaporated to dryness under reduced pressure. The1.4 g of residue were chromatographed over silica gel and was elutedwith a 7-3 cyclohexane-ethyl acetate mixture to obtain 0.932 g of11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one melting at 150° C. and a specific rotation of[α]_(D) ²⁰ =+138.5° (c=0.5% in chloroform).

EXAMPLE 5 11β-[4-trimethylsilyl-phenyl]-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one

STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-(4-trimethylsilylphenyl)-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

200 mg of cuprous chloride were added under an inert atmosphere at -30°C. to 45 ml of solution of 0.65 M of 4-trimethylsilyl-phenyl magnesiumbromide in tetrahydrofuran and a solution of 3.3 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol in 25 ml of tetrahydrofuran were added thereto dropwiseat -20° C. After one hour, the mixture was hydrolyzed with aqueousammonium chloride solution and was extracted with ether. The organicphase was dried and evaporated to dryness under reduced pressure and theresidue was chromatographed over silica gel. Elution with a 94-6methylene chloride-acetone mixture containing 0.1% of triethylamineyielded 2.087 g of3,3-[1,2-ethanediyl-bisoxy]-11β-(4-trimethylsilyl-phenyl)-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol which after crystallization from isopropyl etherand then ethyl acetate melted at 226° C. and a specific rotation of[α]_(D) ²⁰ =-60°±1.5° (c=0.9% in chloroform).

STEP B: 11β-(4-trimethylsilyl-phenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one

1.7 g of Redex sulfonic acid resin were added to a solution of 1.68 g ofthe product of Step A in 17 ml of 90% alcol and the mixture was refluxedfor 30 minutes and vacuum filtered. The filter was rinsed with methylenechloride and the filtrate was evaporated to dryness under reducedpressure. The residue was taken up in methylene chloride and thesolution was dried and evaporated to dryness under reduced pressure. Theresidue was chromatographed over silica gel and was eluted with an 85-15benzene-ethyl acetate mixture to obtain 1.217 g of11β-(4-trimethylsilyl-phenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one melting at 212° C. and having a specificrotation of [α]_(D) ²⁰ =+94° (c=0.9% in chloroform).

The same procedure was used to prepare11β-[3-trimethylsilyl-phenyl]-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰=+52.5±2° (c=1% in chloroform).

EXAMPLE 6 11β-[4-(N,N-dimethylamino)-phenyl]-17β-ethynyl-Δ⁴,9-estradiene-17α-ol-3-one

STEP A: 3,3-dimethoxy-17β-ethynyl-Δ⁵(10),9(11) -estradiene-17α-ol

A mixture of 16.8 g of 3,3-dimethoxy-17α-ethynyl-Δ⁵(10),9(11)-estradiene-17β-ol, 175 ml of anhydrous tetrahydrofuran and 4.35 g oflithium bromide was stirred at room temperature for 5 minutes and thenthe mixture was cooled to -60° C. and 3.9 ml of methane sulfonylchloride were added thereto. The mixture was stirred at -60° C. for onehour and was then poured into 500 ml of aqueous saturated ammoniumchloride solution. The mixture was stirred for 10 minutes and wasextracted with methylene chloride. The organic phase was dried and afterthe addition of 2.5 ml of pyridine, the mixture was evaporated todryness at 0° C. under reduced pressure. 75 ml of tetrahydrofuran wereadded to the residue and 12.5 ml of 0.75 g of silver nitrate in waterwere added thereto. The mixture was held at -30° C. for 18 hours and atroom temperature for 4 hours and was then poured into 500 ml of aqueoussemisaturated ammonium chloride solution containing 5 g of sodiumcyanide. The mixture was stirred at 20° C. for 30 minutes and wasextracted with chloroform. The organic phase was washed with aqueoussaturated sodium chloride solution, dried and evaporated to drynessunder reduced pressure. The residue was chromatographed over silica geland was eluted with a 9-1 petroleum ether-ethyl acetate mixture toobtain 3 g of 3,3-dimethoxy-17β-ethynyl-Δ⁵(10),9(11) -estradiene-17α-olmelting at ˜150° C. and having a specific rotation of [α]_(D) ²⁰=+125°±2.5° (c=1% in chloroform).

STEP B: 3,3-dimethoxy-5α,10α-epoxy-17β-ethynyl-Δ⁹(11) -estrene-17α-ol

0.12 ml of hexachloroacetone and 0.65 ml of oxygenated water (200volumes) were added at 0° C. to a mixture of 2.6 g of the product ofStep A, 12 ml of methylene chloride and one drop of pyridine and themixture was stirred for one hour after which 13 ml of chloroform wereadded. The mixture was stirred for 18 hours and was then poured into 100ml of aqueous saturated sodium thiosulfate solution. The mixture wasstirred for 10 minutes and was extracted with chloroform. The organicphase was washed with aqueous saturated sodium chloride solution, driedand evaporated to dryness under reduced pressure to obtain 2.8 g of3,3-dimethoxy-5α,10α-epoxy-17β-ethynyl-Δ⁹(11) -estrene-17α-ol which wasused as is for the next step. The product contained a small amount ofthe 5β,10β-epoxy compound.

STEP C:3,3-dimethoxy-11β-[4-(N,N-dimethylamino)-phenyl]-17β-ethynyl-.DELTA.⁹-estrene-5α,17α-diol

A mixture of 2.8 g of the product of Step B, 56 ml of anhydroustetrahydrofuran and 80 mg of anhydrous copper chloride was stirred underan inert atmosphere at room temperature for 5 minutes and was thenplaced in an ice bath. 33 ml of 0.95 M 4-dimethylaminophenyl magnesiumbromide in tetrahydrofuran were added dropwise to the mixture which wasthen allowed to return to room temperature.

63 ml of 4-dimethylaminophenyl magnesium bromide were added to asuspension of 6.15 g of dimethylsulfide-copper bromide complex in 30 mlof anhydrous tetrahydrofuran while keeping the temperature below 28.5°C. and the mixture was stirred for 30 minutes. Then, the above solutionwas added dropwise thereto and the mixture was stirred at roomtemperature for 18 hours and was then poured into aqueous saturatedammonium chloride solution. The mixture was stirred for 10 minutes andwas extracted with chloroform. The organic phase was washed with water,dried and evaporated to dryness under reduced pressure. The residue waschromatographed over silica gel and was eluted with a 1-1 petroleumether-ethyl acetate mixture containing 0.5 ppm of triethylamine. The1.28 g of product was chromatographed over silica gel and was elutedwith the same mixture to obtain 0.84 g of3,3-dimethoxy-11β-[4-(N,N-dimethylamino)-phenyl]-17β-ethynyl-.DELTA.⁹-estrene-5α,17α-diol.

STEP D: 11β-[4-(N,N-dimethylamino)-phenyl]-17β-ethynyl-Δ⁴,9-estradiene-17α-ol-3-one

A mixture of 0.76 g of the product of Step C, 15 ml of methanol and 1.6ml of 2 N hydrochloric acid was stirred for 90 minutes and was thenpoured into an aqueous saturated sodium bicarbonate solution. Themixture was extracted with chloroform and the organic phase was driedand evaporated to dryness under reduced pressure. The 0.76 g of residuewas chromatographed over silica gel and was eluted with a 1-1 petroleumether-ethyl acetate mixture and then with a 3-1 ether-petroleum ethermixture to obtain 0.435 g of11β-[4-(N,N-dimethylamino)-phenyl]-17β-ethynyl-Δ⁴,9-estradiene-17α-ol-3-one which after crystallization from isopropylether melted at 142° C. and had a specific rotation of [α]_(D) ²⁰=+235.5°±4.5° (c=0.45% in chloroform).

EXAMPLE 7 11β-[4-(N,N-dimethylamino)-phenyl]-17α-phenyl-Δ⁴,9-estradiene-17β-ol-3-one

STEP A: 3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-Δ⁹(11) -estrene-17-one

2 drops of pyridine were added to a mixture of 11.18 g of3,3-[1,2-ethanediyl-bisoxy]-Δ⁵(10),9(11) -estradiene-17-one and 56 ml ofmethylene chloride and 4.3 ml of hexafluoroacetone sesquihydrate wereadded to the mixture at 0° C. 1.6 ml of 85% oxygenated water were addedto the mixture and the mixture was stirred under an inert atmosphere at0° C. for 23 hours and was poured into a mixture of 200 g of ice and 200ml of 0.5 M sodium thiosulfate solution. The mixture was stirred for 30minutes and was extracted with methylene chloride containing a trace ofpyridine. The organic phase was washed with water, dried and evaporatedto dryness to obtain 11.4 g of3,3-[1,2-ethanediyl-bisoxy]5α,10α-epoxy-Δ⁹(11) -estrene-17-one which wasused as is for the next step.

STEP B:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-.DELTA.⁹-estrene-5α-ol-17-one

A mixture of 200 g of 4-dimethylamino benzene bromide in 950 ml ofanhydrous tetrahydrofuran was added over 21/2 hours at 35° C.±5° C. to amixture of 29 g of magnesium turnings and 50 ml of anhydroustetrahydrofuran under an inert atmosphere to obtain a solution of 0.8 Mof magnesium.

284 ml of the said magnesium solution were added dropwise over 75minutes at 0° to 5° C. under an inert atmosphere to a mixture of 25 g ofthe product of Step A, 500 ml of anhydrous tetrahydrofuran and 0.757 gof copper chloride and the mixture was stirred for 15 minutes and pouredinto aqueous saturated ammonium chloride solution. The mixture wasextracted with ethyl acetate and the organic phase was washed withaqueous saturated ammonium chloride solution and with aqueous saturatedsodium chloride solution, dried and evaporated to dryness under reducedpressure. The 46 g of residue were chromatographed over silica gel andwere eluted with a 1-1 petroleum ether-ethyl acetate mixture containing1 ppm of triethylamine to obtain 17.76 g of product melting at 178° C.The impure fractions were subjected again to chromatography over silicagel and were eluted with an 8-2 petroleum ether-acetone mixturecontaining 1 ppm of triethylamine to obtain another 6.35 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl[-.DELTA.⁹-estrene-5α-ol-17-one melting at 176° C. which was used as is for thenext step.

STEP C:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl[-17.alpha.-phenyl-Δ⁹-estrene-5α,17β-diol

A solution of 4.51 g of the product of Step B in 45.1 ml of anhydroustetrahydrofuran was added over 30 minutes at 25° C. to a solution of33.3 ml of phenyllithium (1.5 moles) and the mixture was stirred for 4hours at room temperature and was then poured into aqueous saturatedammonium chloride solution. The mixture was extracted with ether and theorganic phase was washed with aqueous saturated sodium chloridesolution, dried and evaporated to dryness. The 5.6 g of residue werechromatographed over silica gel and were eluted with a 9-1 methylenechloride-acetone mixture containing 1 ppm of triethylamine to obtain1.16 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-phenyl-Δ⁹-estrene-5α,17β-diol which after crystallization from an isopropylether-methylene chloride mixture melted at 240° C. and had a specificrotation of [α]_(D) ²⁰ =+53°±2.5° (c=0.5 in CHCl₃).

STEP D: 11β-[4-(N,N-dimethylamino)-phenyl]-17α-phenyl-Δ⁴,9-estradiene-17β-ol-3-one

3 ml of 2 N hydrochloric acid were added under an inert atmosphere at 0°to 5° C. to a mixture of 1.5 g of the product of Step C in 45 ml ofmethanol and the mixture was stirred at 0° to 5° C. for one hour. Then,90 ml of ether and 90 ml of an aqueous 0.25 M of sodium bicarbonatesolution were added to the mixture and the mixture was stirred for 5minutes. The decanted aqueous phase was extracted with ether and theorganic phase was washed with aqueous saturated sodium chloridesolution, dried and evaporated to dryness. The 1.3 g of residue werechromatograhed over silica gel and were eluted with a 1-1 petroleumether ether mixture to obtain 0.93 g of11β-[4-(N,N-dimethylamino)-phenyl]-17α-phenyl-Δ⁴,9-estradiene-17β-ol-3-one which after crystallization from methylenechloride-isopropyl ether melted at 226° C. and had a specific rotationof [α]_(D) ²⁰ =+151.5° (c=0.4% in chloroform).

EXAMPLE 811β-[4-(N,N-dimethylamino)-phenyl]-23-methyl-19,21-dinor-17α-.DELTA.⁴,9,23cholatriene-20-yn-17β-ol-3-one

STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-23-methyl-19,21-dinor-17α-Δ⁹,23-choladiene-20-yn-5α,17β-diol

10.61 ml of 2-methyl-1-buten-3-yne were added under an inert atmosphereto a mixture of 4.5 g of potassium tert.-butylate in 90 ml of anhydroustetrahydrofuran and the mixture was stirred for 15 minutes at -10° C. Asolution of 4.5 g of the product of Step B of Example 7 in 45 ml ofanhydrous tetrahydrofuran was added over 15 minutes to the reactionmixture and the mixture was stirred at -10° C. for 30 minutes and thenfor 4 hours at 0° to 5° C. The mixture was poured into 500 ml of aqueoussaturated solution of ammonium chloride and the mixture was extractedwith ethyl acetate. The organic phase was washed with aqueous saturatedsodium chloride solution, dried and evaporated to dryness to obtain 5.56g of raw3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-23-methyl-19,21-dinor-17α-Δ⁹,23-choladiene-20-yn-5α,17β-diol melting at 205° C. which was used as isfor the next step. The raw product was chromatographed over silica geland was eluted with a 9-1 methylene chloride-ethyl acetate containing 1ppm of triethylamine and crystallized from ethyl acetate to obtain theproduct melting at 215° C.

STEP B:11β-[4-(N,N-dimethylamino)-phenyl]-23-methyl-19,21-dinor-17α-.DELTA.⁴,9,23-cholatriene-20-yne-17β-ol-3-one

A mixture of 5 g of the product of Step A, 300 ml of methanol and 10 mlof 2 N hydrochloric acid was stirred under an inert atmosphere for 15minutes at 20° C. and then 300 ml of methylene chloride and then 300 mlof aqueous 0.25 M sodium bicarbonate solution were added thereto. Themixture was stirred for 10 minutes and the decanted aqueous phase wasextracted with methylene chloride. The organic phase was washed withwater, dried and evaporated to dryness. The 4.5 g of residue werechromatographed over silica gel and were eluted with a 1-1 petroleumether-ethyl acetate mixture to obtain after crystallization fromdiisopropyl oxide 2.01 g of11β-[4-(N,N-dimethylamino)-phenyl]-23-methyl-19,21-dinor-17α-.DELTA.⁴,9,23-cholatriene-20-yne-17β-ol-3-one melting at 185° C. and having aspecific rotation of [α]_(D) ²⁰ =+88.5°±1.5° (c=1% in CHCl₃).

EXAMPLE 911β-[4-(N,N-dimethylamino)-phenyl]-17β-methoxy-23-methyl-19,21-dinor-17α-Δ⁴,9,23-cholatriene-20-yne-3-one

10.61 ml of 2-methyl-1-buten-3-yne were added dropwise at -10° C. to asuspension of 4.5 g of potassium tert.-butylate in 90 ml of anhydroustetrahydrofuran under an inert atmosphere and the mixture was stirred at-10° C. for 15 minutes. Then, a mixture of 4.5 g of the product of StepB of Example 7 in 45 ml of anhydrous tetrahydrofuran was added over 15minutes to the mixture which was then stirred at -10° C. for 30 minutesand at 0° to 5° C. for 4 hours. 7.5 ml of methyl iodide were added tothe mixture which was then stirred in an ice bath for 30 minutes andthen poured into 500 ml of 0.1 N hydrochloric acid. The mixture wasstirred for 30 minutes at room temperature and was then extracted withethyl acetate. The organic phase was washed with aqueous saturatedsodium bicarbonate solution, then with aqueous saturated sodium chloridesolution, dried and evaporated to dryness. The residue waschromatographed over silica gel and was eluted with a 95-5 methylenechloride-ethyl acetate mixture to obtain 2.7 g of11β-[4-(N,N-dimethylamino)-phenyl]-17β-methoxy-23-methyl-19,21-dinor-17α-Δ⁴,9,23-cholatriene-20-yne-3-one which after crystallization from methanolmelted at 105° C.

EXAMPLE 1011β-[4-(N,N-dimethylamino)-phenyl]21-chloro-19-nor-17α-Δ.sup.4,9-pregnadiene-20-yne-17β-ol-3-one

STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁹-pregnene-20-yne-5α,17β-diol

A solution of 7 ml of trichloroethylene in 28 ml of anhydrous ether wasadded with stirring under an inert atmosphere at 0° to 5° C. to amixture of 77.5 ml of 1 M butyllithium in hexane and 310 ml of anhydrousether and the mixture was stirred for one hour while the temperaturerose to 20° C. A solution of 7 g of Step B of Example 7 in 70 ml oftetrahydrofuran was added to the resulting mixture dropwise over 30minutes at 0° to 5° C. and the mixture was stirred at 0° to 5° C. for 30minutes after which the temperature was allowed to rise to 20° C. andwas slowly poured into an aqueous saturated ammonium chloride solutionand the decanted aqueous phase was extracted with methylene chloride.The organic phase was washed with water, dried and evaporated to drynessto obtain 8.5 g of raw product melting at 220° C. The latter was addedto 42.5 ml of diisopropyl oxide and the mixture was stirred for 30minutes and vacuum filtered to obtain 6.38 g of product melting at 230°C. The latter was chromatograhed over silica gel and was eluted with a7-3 benzene-ethyl acetate mixture containing 1 ppm of triethylamine. Theproduct was dissolved in methylene chloride and was precipitated byaddition of diisopropyl oxide to obtain3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁹-pregnene-20-yne-5α,17β-diol melting at 240° C. and having a specificrotation of [α]_(D) ²⁰ =-83.5°±1.5° (c=1% in CHCl₃).

STEP B: 11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁴,9-pregnadiene-20-yne-17β-ol-3-one

15 ml of 2 N hydrochloric acid were added under an inert atmosphere to amixture of 6.38 g of the product of Step A in 191.4 ml of 95% ethanoland after stirring the mixture for one hour, 300 ml of methylenechloride and then 200 ml of aqueous 0.25 mm sodium bicarbonate solutionwere added thereto. The decanted aqueous phase was extracted withmethylene chloride and the organic phase was washed with water, driedand evaporated to dryness under reduced pressure. The 6 g of residuewere chromatographed over silica gel and were eluted with a 7-3benzene-ethyl acetate mixture to obtain 3.95 g of11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁴,9-pregnadiene-20-yne-17β-ol-3-one which after crystallization from ethylacetate melted at 240° C. and had a specific rotation of [α]_(D) ²⁰=+111°±2° (c=1% in chloroform).

EXAMPLE 11 N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁴,9-pregnadiene-20-yne-17β-ol-3-one

A mixture of 0.54 g of 85% M-chloroperbenzoic acid in 10.8 ml ofmethylene chloride was added under an inert atmosphere at 0° to 5° C. toa mixture of 1.2 g of the product of Example 10 in 24 ml of methylenechloride and the mixture was stirred for one hour at 0° to 5° C. and wasthen poured into aqueous 0.2 N sodium thiosulfate solution. The mixturewas extracted with methylene chloride and the organic phase was washedwith aqueous saturated sodium bicarbonate solution, with water, driedand evaporated to dryness. The 1.3 g of residue was chromatographed oversilica gel and was eluted with a 7-3 methylene chloride-methanol mixtureto obtain 1.15 g of N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁴,9-pregnadiene-20-yne-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰=+47.5°±1.5° (c= 0.7% in chloroform).

EXAMPLE 12 N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-9α,10α-epoxy-21-chloro-19-nor-17α-Δ⁴-pregnene-20 -yne-17β-ol-3-one

A mixture of 1.17 g of 85% m-chloroperbenzoic acid in 23.4 ml ofmethylene chloride was added over 15 minutes at 0° to 5° C. to asolution of 1.18 g of the product of Example 10 in 23.6 ml of methylenechloride and the mixture was stirred for 2 hours at 20° C. after whichanother 1.17 g of 85% M-chloroperbenzoic acid were added. The mixturewas stirred for one hour and was poured into a solution of aqueous 0.2 Nsodium thiosulfate. The mixture was extracted with methylene chlorideand the organic phase was washed with aqueous saturated sodiumbicarbonate solution and then with water, dried and evaporated todryness to obtain 1.14 g of residue melting at 220° C. The residue waschromatographed over silica gel and was eluted with an 8-2 methylenechloride-methanol mixture to obtain 1 g of N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-9α,10α-epoxy-21-chloro-19-nor-17α-Δ⁴-pregnene-20-yne-17β-ol-3-one melting at 270° C. and having a specificrotation of [α]_(D) ²⁰ =+39.5°±2.5° (c=0.5% in chloroform).

EXAMPLE 139α,10α-epoxy-11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁴-pregnene-20-yne-17β-ol-3-one

0.34 g of triphenylphosphine were added under an inert atmosphere to amixture of 0.63 g of the product of Example 12 in 6.3 ml of acetic acidand the mixture was stirred at room temperature for 45 minutes and wasthen poured into water. The mixture was extracted with methylenechloride and the organic phase was washed with water, dried andevaporated to dryness. The 0.9 g of residue was chromatographed oversilica gel and was eluted with a 1-1 petroleum ether-ethyl acetatemixture. The product was crystallized from a methylenechloride-isopropyl ether mixture to obtain 0.346 g of9α,10α-epoxy-11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁴-pregnene-20-yne-17β-ol-3-one melting at 265° C. and having a specificrotation of [α]_(D) ²⁰ =+45°±2° (c=0.8% in chloroform).

EXAMPLE 1411β-[4-(N,N-dimethylamino)-phenyl]-21-phenyl-19-nor-17α-Δ.sup.4,9-pregnadiene-20-yne-17β-ol-3-one

STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-21-phenyl-19-nor-17α-Δ⁹-pregnene-20-yne-5α,17β-diol

A mixture of 4.17 g of potassium tert.-butylate in 83 ml of anhydroustetrahydrofuran was stirred under an inert atmosphere for 10 minutes andthen 4.5 ml of phenyl acetylene were added dropwise at -10° C. Thesuspension was stirred for 5 minutes and then a solution of 4.17 g ofthe product of Step B of Example 7 in 41 ml of anhydrous tetrahydrofuranwas added thereto dropwise at -10° C. Then, the temperature rose to 0°C. and held there for one hour and was then poured into an aqueoussaturated ammonium chloride solution. The mixture was extracted withether and the organic phase was washed with aqueous saturated sodiumchloride solution, dried and evaporated to dryness. The 4.7 g of residuewere chromatographed over silica gel and eluted with a 95-5 methylenechloride-acetone mixture to obtain 3.71 of of3,3-[1,2-ethanediyl-bisoxy]-11β-[4,(N,N-dimethylamino-phenyl]-21-phenyl-19-nor-17α-Δ.sup.9 -pregnene-20-yne-5α,17β-diol melting at 168° C. and having a specificrotation of [α]_(D) ²⁰ =-119.5°±2° (c=1% in chloroform).

STEP B: 11β-[4-(N,N-dimethylamino)-phenyl]-21-phenyl-19-nor-17α-Δ⁴,9-pregnadiene-20-yne-17β-ol-3-one

6.3 ml of 2 N hydrochloric acid were added to a solution of 3.49 g ofthe product of Step A in 68 ml of methanol and the mixture was stirredfor 30 minutes and was poured into a mixture of 180 ml of ether and 90ml of aqueous 0.25 M sodium bicarbonate solution. The mixture wasstirred for 5 minutes and the decanted aqueous phase was extracted withether. The organic phase was washed with aqueous 0.25 M sodiumbicarbonate solution, then with aqueous sodium chloride, dried andevaporated to dryness. The 4.35 g of residue were chromatographed oversilica gel and eluted with with a 95-5 methylene chloride-acetonemixture to obtain 2.13 g of11β-[4-(N,N-dimethylamino)-phenyl]-21-phenyl-19-nor-17α-Δ⁴,9-pregnadiene-20-yne-17β-ol-3-one which after crystallization fromisopropyl ether had a specific rotation of [α]_(D) ²⁰ =+22.5°±1° (c=1%in chloroform).

EXAMPLE 15 11β-[4-(N,N-dimethylamino)-phenyl]-17α-(propa-1,2-dienyl)-Δ⁴,9 -estradiene-17β-ol-3-one

STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)phenyl]-17.alpha.-(propa-1,2-dienyl)-Δ⁹-estrene-5α,17β-diol and3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-2-ynyl)-Δ⁹-estrene-5α,17β-diol

Allene was bubbled into 50 ml of anhydrous tetrahydrofuran at 0° to 5°C. until 2,1 g were absorbed and 23.9 ml of a solution of a 1.3 M ofbutyllithium in hexane were added thereto over 15 minutes at -70° C. Themixture was stirred at -70° C. for 15 minutes and then a solution of 3.5g of the product of Step B of Example 7 in 35 ml of anhydroustetrahydrofuran were added thereto at -70° C. over 25 minutes. Themixture was stirred at -70° C. for one hour and was poured slowly intoan iced aqueous saturated ammonium chloride solution. The mixture wasextracted with ether and the organic phase was washed with aqueoussaturated sodium chloride solution, dried and evaporated to dryness. The3.4 g of residue were chromatographed over silica gel and eluted with a1-1 petroleum ether-ethyl acetate mixture containing 1 ppm oftriethylamine to obtain 1.73 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(propa-1,2l-dienyl)-Δ⁹ -estrene-5α,17β-diol melting at 178° C. and having aspecific rotation of [α]_(D) ²⁰ =-32°±2° (c=0.7% in chloroform) and 1.5g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-2-ynyl)-Δ⁹ -estrene-5α,17β-diol melting at 150° C. and having a specificrotation of [α]_(D) ²⁰ =-15°+2° (c=0.9% in chloroform).

STEP B:11β-[4-(N,N-dimethylamino)-phenyl]-17α-(propa-1,2-dienyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one

A mixture of 1.73 g of the 17α-(propa-1,2-dienyl)-isomer of Step A, 51.8ml of 95% ethanol and 3.5 ml of 2 N hydrochloric acid was stirred underan inert atmosphere at 20° C. for one hour and then 50 ml of methylenechloride and 50 ml of aqueous 0.25 M sodium bicarbonate solution wereadded thereto. The decanted aqueous phase was extracted with methylenechloride and the organic phase was washed with water, dried andevaporated to dryness. The 1.51 g of residue were dissolved in 10 ml ofhot methylene chloride and 15 ml of isopropyl ether were added to thesolution. The mixture was concentrated and allowed to stand to obtain1.23 g of product which were crystallized form a methylenechloride-isopropyl ether mixture to obtain 1.11 g of11β-[4-(N,N-dimethylamino)-phenyl]-17α-(propa-1,2-dienyl)-.DELTA.⁴,9-estradiene 17β-ol-3-one melting at 228° C. and having a specificrotation of [α]_(D) ²⁰ =+139.5°±3° (c=0.8% in chloroform).

EXAMPLE 1611β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-2-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

A mixture of 0.94 g of the 17α-(prop-2-ynyl)-isomer of Step A of Example15, 28.2 ml of 95% ethanol and 2 ml of 2 N hydrochloric acid was stirredat 20° C. for one hour and then 50 ml of methylene chloride and 50 ml ofan aqueous 0.25 M sodium bicarbonate solution were added thereto. Themixture was stirred for 5 minutes and the decanted aqueous phase wasextracted with methylene chloride. The organic phase was washed withwater, dried and evaporated to dryness and the residue waschromtographed over silica gel. Elution with a 1-1 petroleum ether-ethylacetate mixture yielded 0.42 g of11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-2-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰=+143°±3° (c=0.8% in chloroform).

EXAMPLE 17 11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethynyl-Δ⁴,9-estradiene 17β-ol-3-one

STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.beta.-cyano-17α-trimethylsilyloxy-Δ⁹-estrene-5α-ol

A solution of 18 mmoles of [4-(N,N-dimethylamino)-phenyl]-magnesiumbromide in anhydrous tetrahydrofuran was added under an inert atmosphereto a suspension of 2.05 g of dimethylsulfide-copper bromide complex in10 ml of anhydrous tetrahydrofuran and the mixture was stirred for 30minutes after which 20 ml of anhydrous triethylamine were added thereto.A solution of 0.95 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17β-cyano-17.alpha.-trimethylsilyloxy-Δ⁹(11)-estrene in anhydrous tetrahydrofuran were added to the mixture whichwas then stirred for 15 hours at room temperature and poured into 50 mlof aqueous saturated ammonium chloride solution. The decanted aqueousphase was extracted with ether and the organic phase was washed withwater, dried and evaporated to dryness. The residue was chromatographedover silica gel and was eluted with an 8-2 benzene-ethyl acetate mixtureto obtain 1.1 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.beta.-cyano-17α-trimethylsilyloxy-Δ⁹-estrene-5α -ol which after crystallization from isopropyl ether meltedat 247° C. and had a specific rotation of [α]_(D) ²⁰ =-12.5° (c=1% inchloroform).

STEP B:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-ethynyl-Δ⁹-estrene-5α,17β-diol

1 g of the acetylide complex of lithium ethylenediamine was added to amixture of 0.8 g of the product of Step A in 8 ml of ethylenediamine andthe mixture was stirred under an inert atmosphere at ˜50° C. for 90minutes. The mixture was cooled to 20° C. and was poured into aqueousammonium chloride solution. The mixture was extracted with ether andmethylene chloride and the organic phase was dried and evaporated todryness. The residue was chromatographed over silica gel and was elutedwith a 7-3 benzene-ethyl acetate mixture. The product was crystallizedfrom isopropyl ether to obtain 0.43 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-ethynyl-Δ⁹-estrene-5α,17β-diol melting at 199° C. and having a specific rotationof [α]_(D) ²⁰ =-43°±1.5° (c=1% in chloroform).

STEP C: 11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethynyl-Δ⁴,9-estradiene-17β-ol-3-one

1 ml of 2 N hydrochloric acid was added to a solution of 0.25 g of theproduct of Step B in 6 ml of methanol and the mixture was stirred at 20°C. for 40 minutes and then was poured into water containing 2.5 ml of Nsodium hydroxide. The mixture was extracted with ether and the organicphase was dried and evaporated to dryness. The residue waschromatographed over silica gel and was eluted with a 7-3 benzene-ethylacetate mixture to obtain 0.25 of11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethynyl-Δ⁴,9-estradiene-17β-ol-3-one.

Analysis: C₂₈ H₃₃ NO₂ ; molecular weight=415.54 Calculated: %C, 80.92;%H, 8.00; %N, 3.37. Found: %C, 80.7; %H, 8.1; %N, 3.1.

EXAMPLE 18 11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethynyl-Δ⁴,9-estradiene-17β-ol-3-one

STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-ethynyl-Δ⁹-estrene-5α,17β-diol

12.25 g of the acetylide complex of lithium ethylenediamine were addedunder an inert atmosphere to a solution of 6 g of the product of Step Bof Example 7 in 180 ml of tetrahydrofuran and the mixture was stirred at55° C. for 4 hours and was then cooled and poured into 600 ml of an icedaqueous saturated ammonium chloride solution. The mixture was extractedwith ether and the organic phase was washed with aqueous saturatedsodium chloride solution, dried and evaporated to dryness. The residuewas chromatographed over silica gel and eluted with a 7-3 benzene-ethylacetate mixture containing 1 ppm of triethylamine. The 4.5 g of productwas crystallized from a methylene chloride-diisopropyl oxide mixture toobtain3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-ethynyl-Δ⁹-estrene-5α,17β-diol melting at 202° C. and having a specific rotationof [α]_(D) ²⁰ =-47.5°±1.5° (c=1% in chloroform).

STEP B: 11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethynyl-Δ⁴,9-estradiene-17β-ol-3-one

5 ml of 2 N hydrochloric acid were added to a suspension of 2 g of theproduct of Step A in 50 ml of 95% ethanol and the mixture was stirred at20° C. for one hour. 100 ml of ether and then 100 ml of aqueous. 0.25 Msodium bicarbonate solution were added to the mixture and the decantedaqueous phase was extracted with ether. The organic phase was washedwith aqueous saturated sodium chloride solution, dried and evaporated todryness and the residue was chromatographed over silica gel. Elutionwith a 6-4 petroleum ether-ethyl acetate mixture yielded 1.52 g of11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethynyl-Δ⁴,9-estradiene-17β-ol-3-one which after crystallization from diisopropyloxide melted at 172° C. and had a specific rotation of [α]_(D) ²⁰=+182°±2.5° (c=1% in chloroform).

EXAMPLE 19 11β-[3-(N,N-dimethylamino)-phenyl]-17α -(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one

STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[3-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A mixture of 10 g of m-bromo-dimethylaniline in 45 ml of anhydroustetrahydrofuran was added under an inert atmosphere over 45 minutes to amixture of 1.46 g of magnesium and 5 ml of anhydrous tetrahydrofuran andthe reaction was started by addition of dibromomethane. The mixture wasstirred for one hour to obtain a solution of 0.95 M of magnesium and42.2 ml of the solution were added at 0° to 5° C. over 30 minutes underan inert atmosphere to a mixture of 3.7 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17βl -ol, 74 ml of anhydrous tetrahydrofuran and 99 mg ofcopper chloride and the mixture was stirred for 30 minutes at 0° to 5°C. and was poured into an aqueous saturated ammonium chloride solution.The mixture was extracted with ether and the organic phase was washedwith aqueous saturated sodium chloride solution, dried and evaporated todryness. The residue was chromatographed over silica gel and eluted witha 9-1 methylene chloride-acetone mixture containing 1 ppm oftriethylamine to obtain 3.5 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[3-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ⁹ -estrene-5α,17β-diol melting at 262° C. and havinga specific rotation of [α]_(D) ²⁰ =-64°±1.5° (c=1% in chloroform) and0.66 g of the corresponding 5β-ol isomer melting at 210° C. and having aspecific rotation of [α]_(D) ²⁰ =+32.5°±1° (c=0.8% in chloroform).

STEP B: 11β-[3-(N,N-dimethylamino)-phenyl]-b 17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one

10 ml of 2 N hydrochloric acid were added at 0° to 5° C. under an inertgas to a mixture of 3.3 g of the product of step A in 100 ml of methanoland the mixture was stirred at 0° to 5° C. for one hour. 200 ml ofdiethyl oxide and then 200 ml of aqueous 0.25 M sodium bicarbonatesolution were added to the mixture which was then stirred for 5 minutes.The decanted aqueous phase was extracted with diethyloxide and theorganic phase was washed with aqueous saturated sodium chloridesolution, dried and evaporated to dryness. The 3 g of residue werechromatographed over silica gel and eluted with a 7-3 benzene-ethylacetate mixture to obtain 1.43 g of amphorous11β-[3-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰=+43°±2.5° (c=1% in CHCl₃).

EXAMPLE 20 N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

A solution of 0.71 g of 85% m-chloroperbenzoic acid in 14.2 ml ofmethylene chloride was added over 10 minutes at 0° to 5° C. to a mixtureof 1.5 g of the product of Example 4 in 30 ml of methylene chloride andthe mixture was stirred for one hour at 0° to 5° C. and was poured into100 ml of an aqueous 0.2 N sodium thiosulfate solution. The decantedaqueous phase was extracted with methylene chloride and the organicphase was washed with aqueous 0.5 M sodium bicarbonate solution, driedand evaporated to dryness. The residue was dissolved in 20 ml ofmethylene chloride and 20 ml of diisopropyl oxide were added thereto.Crystallization was induced and the mixture stood for a while and wasvacuum filtered. The crystals were dried to obtain 1.4 g of N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3 -one melting at 210° C. and having a specificrotation of [α]_(D) ²⁰ =+73.5°±2° (c=1% in chloroform).

EXAMPLE 21 11β-[4-(N,N-dimethylamino)-phenyl]-Δ⁴,9-estradiene-17β-ol-3-one

106 mg of sodium borohydride were added to a solution of 1 g of theproduct of Step B of Example 7 in 20 ml of tetrahydrofuran containing10% water and the mixture was stirred for one hour and poured into 200ml of water. The mixture was extracted with methylene chloride and theorganic phase was washed with aqueous saturated sodium chloridesolution, dried and evaporated to dryness to obtain 1.3 g of11β-[4-(N,N-dimethylamino)-phenyl]-Δ⁴,9 -estradiene-5α,17β-diol-3-one.0.63 g of the latter were added to a mixture of 12 ml of methanol and2.4 ml of 2 N hydrochloric acid and the mixture was stirred at roomtemperature for 90 minutes and was poured into aqueous sodiumbicarbonate. The mixture was extracted with ether and the organic phasewas washed with aqueous saturated sodium chloride solution, dried andevaporated to dryness. The residue was chromatographed over silica geland was eluted with a 6-4 petroleum ether-ethyl acetate mixture. Theresidue was triturated with petroleum ether and vacuum filtered toobtain 0.38 g of 11β-[4-(N,N-dimethylamino)-phenyl]-Δ⁴,9-estradiene-17β-ol-3-one melting at 130° C. and having a specificrotation of [α]_(D) ²⁰ =+277°±5° (c=0.5% in chloroform).

EXAMPLE 2211β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-2-enyl)-Δ.sup.4,9-estradien-17β-ol-3-one

STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-2-enyl)-Δ⁹-estrene-5α,17β-diol

A solution of 3.5 g of the product of Step B of Example 7 in 35 ml oftetrahydrofuran was added under an inert atmosphere at 20° C. over 15minutes to 55.5 ml of 0.7 M allyl magnesium bromide in ether and themixture was stirred at 20° C. for one hour and was then poured into anaqueous saturated ammonium chloride solution. The mixture was extractedwith ether and the organic phase was washed with aqueous saturatedsodium chloride solution, dried and evaporated to dryness. The residuewas dissolved in 10 ml of methylene chloride and 15 ml of diisopropyloxide were added to the solution which was then concentrated and allowedto stand. The mixture was vacuum filtered and the crystals were rinsedwith diisopropyl oxide and dried to obtain 2.76 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-2-enyl)-Δ⁹-estrene-5α,17β-diol melting at 198° C.

Analysis: C₃₁ H₄₃ NO₄ ; molecular weight=493.69 Calculated: %C, 74.42;%H, 8.78; %N, 2.83. Found: %C, 74.0; %H, 8.7; %N, 2.9.

STEP B: 11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-2-enyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

4.5 ml of 2 N hydrochloric acid were added to a suspension of 2.2 g ofthe product of Step A in 66 ml of methanol and the mixture was stirredat 20° C. for 30 minutes after which 132 ml of diethyl oxide and then132 ml of aqueous 0.25 M sodium bicarbonate solution were added thereto.The decanted aqueous phase was extracted with diethyl oxide and theorganic phase was washed with aqueous saturated sodium chloridesolution, dried and evaporated to dryness. The residue waschromatographed over silica gel and was eluted with a 7-3 benzene-ethylacetate mixture. The product was taken up in a mixture of 15 ml ofdiisopropyl oxide and 7.5 ml of methylene chloride and the solution wasconcentrated and allowed to stand. The mixture was vacuum filtered andthe crystals were rinsed with diisopropyl oxide and dried to obtain1.365 g of11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-2-enyl)-Δ.sup.4,9-estradiene-17β-ol-3-one melting at 182° C. and having a specificrotation of [α] _(D) ²⁰ =+206.5°±3° (c=1% in chloroform).

EXAMPLE 2311β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one

STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A solution of 42.8 g of 4-(N,N-dimethylaminomethyl)bromobenzene in 190ml of anhydrous tetrahydrofuran was added over 90 minutes under an inertatmosphere at 45° to 50° C. to a mixture of 5.5 g of magnesium in 10 mlof anhydrous tetrahydrofuran and the reaction was induced withdibromoethane addition. The mixture was stirred for one hour to obtainan 0.85 M magnesium solution and 127 ml of the said solution were addedunder an inert atmosphere at 0° to 5° C. over one hour to a mixture of10 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol, 200 ml of anhydrous tetrahydrofuran and 0.27 g ofcopper chloride. The mixture was stirred for 15 minutes and was pouredinto an aqueous saturated ammonium chloride solution. The mixture wasextracted with ether and the organic phase was washed with aqueoussaturated sodium chloride solution, dried and evaporated to dryness. Theresidue was chromatographed over silica gel and was eluted with a 9-1methylene chloride-methanol mixture containing 1 ppm of triethylamine toobtain 10.1 g of product. The latter was dissolved in methylene chlorideand a few drops of methanol and then diisopropyl oxide were addedthereto. The mixture was concentrated, allowed to stand for 6 hours andwas vacuum filtered to obtain 7.37 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol melting at 186° C. and having a specific rotationof [α]_(D) ²⁰ =-63°±2.5° (c=0.5% in chloroform).

STEP B:11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one

A mixture of 15 ml of 2 N hydrochloric acid, 7.37 g of the product ofStep A and 147.4 ml of methanol was stirred at 20° C. for one hour andthen 300 ml of diethyl oxide and 300 ml of aqueous 0.25 M sodiumbicarbonate solution were added thereto. The decanted aqueous phase wasextracted with diethyl oxide and the organic phase was washed withaqueous saturated sodium chloride solution, dried and evaporated todryness. The product was dissolved in a mixture of diisopropyl oxide andmethylene chloride and the solution was concentrated and allowed tostand. The mixture was vacuum filtered and the crystals were dried toobtain 3.74 g of11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one melting at 190° C. and having a specificrotation of [α]_(D) ²⁰ =+84.5°±2° (c=0.8% in chloroform).

EXAMPLE 24 11β-(4-pyrrolidinyl-phenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one

STEP A:3,3-[1,2-ethanediyl-bisoxyl]-11β-(4-pyrrolidinylphenyl)-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A solution of 34 g of 4-pyrrolidinyl-bromobenzene in 140 ml of anhydroustetrahydrofuran was added over one hour under an inert atmosphere at45°-50° C. to a mixture of 4 g of magnesium and 10 ml of anhydroustetrahydrofuran and the reaction was started by addition ofdibromoethane to obtain a 1 M magnesium solution. 86.4 ml of the saidsolution were added over 90 minutes at 0° to 5° C. under an inertatmosphere to a mixture of 8 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol in 160 ml of anhydrous tetrahydrofuran and 216 mg ofcopper chloride and the mixture was stirred for one hour and was pouredinto an aqueous saturated ammonium chloride solution. The mixture wasextracted with diethyl oxide and the organic phase was washed withaqueous saturated ammonium chloride solution, aqueous saturated sodiumchloride solution, dried and evaporated to dryness. The residue waschromatographed over silica gel and was eluted with a 95-5 methylenechloride-acetone mixture containing 1 ppm of triethylamine to obtain 8.3g of3,3-[1,2-ethanediylbisoxyl]-11β-(4-pyrrolidinyl-phenyl)-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol which after crystallization from a methylenechloride-isopropyl ether mixture melted at 185° C. and had a specificrotation of [α]_(D) ²⁰ =-67°±1.5° (c=1% in chloroform).

STEP B: 11β-(4-pyrrolidinyl-phenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one

A mixture of 13 ml of 2 N hydrochloric acid, 6.4 g of the product ofStep A and 128 ml of methanol was stirred at 20° C. for one hour andthen 256 ml of diethyl oxide and 256 ml of aqueous 0.25 M sodiumbicarbondate solution were added thereto. The decanted aqueous phase wasextracted with diethyl oxide and the organic phase was washed withaqueous 0.25 M sodium bicarbonate solution, with aqueous saturatedsodium chloride solution, dried and evaporated to dryness. The residuewas chromatographed over silica gel and was eluted with a 1-1 petroleumether-ethyl acetate mixture to obtain 5.25 g of11β-(4-pyrrolidinyl-phenyl)-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one which after crystallization from a methylenechloride-diisopropyl oxide mixture melted at 190° C. and had a specificrotation of [α]_(D) ²⁰ =+120°±2.5° (c=1.2% in chloroform).

EXAMPLE 25 11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethenyl-Δ⁴,9-estradiene-17β-ol-3-one

STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-ethenyl-Δ⁹-estrene-5α,17β-diol

A current of hydrogen was passed for one hour through a mixture of 3 gof the product of Step B of Example 17, 60 ml of anhydrous pyridine and0.6 g of 5% palladized calcium carbonate at room temperature and themixture was then vacuum filtered. The filtrate was evaporated to drynessand the residue was taken up in toluene. The solution was evaporated todryness to obtain 2.94 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-ethenyl-Δ⁹-estrene-5α,17β-diol melting at 181° C. which was used as is for thenext step. A sample after crystallization from a mixture of methylenechloride-diisopropyl oxide melted at 182° C. and had a specific rotationof [α]_(D) ²⁰ =-6.5°±2° (c=0.7% in chloroform).

STEP B: 11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethenyl-Δ⁴,9-estradiene-17β-ol-3-one

A mixture of 6.2 ml of 2 N hydrochloric acid, 2.94 g of the product ofStep A and 60 ml of methanol was stirred at 20° C. for one hour and then120 ml of ether and 120 ml of aqueous 0.25 M sodium bicarbonate solutionwere added thereto. The mixture was stirred for 10 minutes and thedecanted aqueous phase was extracted with ether. The organic phase waswashed with aqueous 0.25 M sodium bicarbonate solution, aqueoussaturated sodium chloride solution, dried and evaporated to dryness. The2.65 g of residue were chromatographed over silica gel and eluted with a7-3 benzene-ethyl acetate mixture. The product was crystallized from adiisopropyl oxide-methylene chloride mixture to obtain 1.51 g of11β-[4-(N,N-dimethylamino)-phenyl]-17α-ethenyl-Δ⁴,9-estradiene-17β-ol-3-one melting at 150° C. and having a specificrotation of [α]_(D) ²⁰ =+243°±3° (c=0.8% in chloroform).

EXAMPLE 26 11β-[4-(N,N-diethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

STEP A: 4-(N,N-diethylamino)-bromobenzene

93 g of bromine were added dropwise to a solution of 86 g ofN,N-diethylaniline in 400 ml of acetic acid and the mixture was pouredinto an ice-water mixture. The mixture was extracted with methylenechloride and the organic phase was washed with aqueous sodiumbicarbonate solution, dried and evaporated to dryness to obtain 125 g of4-(N,N-diethylamino)-bromobenzene boiling at 97° C. at 0.6 mm Hg.

STEP B:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-diethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A solution of 34.2 g of 4-(N,N-diethylamino)-bromobenzene in 110 ml oftetrahydrofuran was added at 35° C. under an inert atmosphere to amixture of 3.9 g of magnesium and 10 ml of tetrahydrofuran to obtain a 1M magnesium solution and 80 ml of the said solution was slowly addedwith stirring at 0° to 5° C. under an inert atmosphere to a solution of7.4 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol, 150 ml of anhydrous tetrahydrofuran and 0.25 g ofcopper chloride. The mixture was stirred at 20° C. for 17 hours and wasthen poured into an aqueous ammonium chloride solution. The mixture wasextracted with ether and the organic phase was washed with aqueoussodium bicarbonate solution, dried and evaporated to dryness. Theresidue was empasted with petroleum ether and treated with activatedcarbon in ether. The product was crystallized from isopropyl ether toobtain 4 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-diethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-Δ⁶-estrene-5α,17β-diol with a specific rotation of [α]_(D) ²⁰ =-61°±2.5°(c=0.7% in CHCl₃).

STEP C: 11β-[4-(N,N-diethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

A mixture of 8 ml of 2 N hydrochloric acid, 3.12 g of the product ofStep B and 45 ml of methanol was stirred at 20° C. under an inertatmosphere for 45 minutes and was then poured into water. The mixturewas neutralized by addition of 2 N sodium hydroxide solution and wasextracted with methylene chloride. The organic phase was dried andevaporated to dryness and the residue was chromatographed over silicagel. Elution with a 1-1 benzene-ethyl acetate mixture yielded 1.34 g of11β-[4-(N,N-diethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰=+144.5°±3° (c=0.8% in chloroform).

Analysis: C₃₁ H₃₉ NO₂ ; molecular weight=457.63 Calculated: %C, 81.36;%H, 8.59; %N, 3.06. Found: %C, 81.7; %H, 8.8; %N, 2.09.

EXAMPLE 2711β-[4-(N-methyl-N-3-methylbutylamino)-phenyl]-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one

STEP A: N-methyl-N-(3-methylbutyl)-aniline

121 g of isoamyl bromide were added dropwise to a mixture of 86 g ofN-methyl-aniline, 500 ml of anhydrous benzene and 81 g of anhydroustriethylamine and the mixture was refluxed for 100 hours and wasfiltered. The filtrate was washed with water, dried and evaporated todryness. The residue was distilled to obtain 90 g ofN-methyl-N-(3-methylbutyl)-aniline boiling at 132° C. at 18 mm Hg.

STEP B: N-methyl-N-(3-methylbutyl)-4-bromo-aniline

A solution of 58 g of bromine in 60 ml of acetic acid was added dropwiseat about 15° C. over one hour to a mixture of 64 g of the product ofStep A in 300 ml of acetic acid and the mixture was stirred at 80° C.for 8 hours and was poured into iced water. The mixture was extractedwith methylene chloride and the organic phase was washed with aqueoussodium bicarbonate, with water, dried and evaporated to dryness. Theresidue was distilled to obtain 70 g ofN-methyl-N-(3-methylbutyl)-4-bromo-aniline boiling at 119° C. at 0.5 mmHg.

STEP C:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N-methyl-N-3-methylbutylamino)-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A few ml of a solution of the product of Step B in tetrahydrofuran wereadded under an inert atmosphere to a mixture of 4.12 g of magnesium and10 ml of tetrahydrofuran and the reaction was started by addition of 0.2ml of 1,2-dibromoethane. The rest of the solution of the product of StepB in anhydrous tetrahydrofuran (32.6 g in 90 ml) was added over 40minutes to the mixture and after the temperature returned to roomtemperature, the mixture was stirred for one hour to obtain an 0.9 Mmagnesium solution. A mixture of 3.77 g of copper chloride, 8 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol and 90 ml anhydrous tetrahydrofuran was stirred under aninert atmosphere at 5° C. for 20 minutes and then 100 ml of themagnesium solution were added thereto. The mixture was poured intoaqueous ammonium chloride solution and was extracted with ethercontaining triethylamine and then with methylene chloride containingtriethylamine. The combined organic phases were washed with aqueoussaturated sodium chloride solution, dried and evaporated to dryness toobtain 31.2 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N-methyl-N-3-methylbutylamino)-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol which was used as is for the next step. A sample ofthe product was chromatographed over silica gel and was eluted with a96.5-4.5-0.5 methylene chloride-acetone-triethylamine mixture to obtainthe compound with a specific rotation of [α]_(D) ²⁰ =-59.5°±2.5° (c=0.7%in chloroform).

STEP D:11β-[4-(N-methyl-N-(3-methyl-butyl)-amino)-phenyl]-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one

A mixture of 52 ml of 2 N hydrochloric acid, 26 g of the product of StepC and 200 ml of methanol was stirred for one hour and was then pouredinto aqueous sodium bicarbonate. The mixture was extracted with etherand then methylene chloride and the combined organic phases were washedwith aqueous saturated sodium chloride solution, dried and evaporated todryness. The residue was chromatographed over silica gel and was elutedwith an 92-8 toluene-ethyl acetate mixture to obtain 3.23 g of11β-[4-(N-methyl-N-(3-methyl-butyl)-amino)-phenyl]-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17βol-3-one with a specific rotation of [α]_(D) ²⁰=+125°±3.5° (c=0.6% in chloroform).

Analysis: C₃₃ H₄₃ NO₂ ; molecular weight=485.71 Calculated: %C, 81.6;%H, 8.92; %N, 2.88. Found: %C, 81.4; %H, 9.0; %N, 2.7.

EXAMPLE 2811β-[4-(N,N-dimethylaminoethylthio)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one

STEP A: 4-(N,N-dimethylaminoethylthio)-bromobenzene

A solution of 23.5 g of chloroethyldimethylamine.HCl in 75 ml of ethanolwas added to 160 ml of sodium hydroxide solution formed by dissolving 20g of sodium hydroxide pastilles in 500 ml of ethanol. A solution of 30 gof 4-bromothiophenol in 100 ml of ethanol was added to 160 ml of thesaid sodium hydroxide solution and the first solution was added theretoover 2 minutes at 20° C. The mixture was refluxed for 3 hours and wasevaporated to dryness. Water was added to the residue and the mixturewas extracted with methylene chloride. The organic phase was washed withaqueous 0.1 N sodium hydroxide solution, then with water, dried andevaporated to dryness. The residue was distilled to obtain 35.5 g of4-(N,N-dimethylaminoethylthio)-bromobenzene boiling at 110° C. at 0.1 mmHg.

STEP B:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminoethylthio)-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol

A solution of 20 g of the product of Step A in 40 ml of anhydroustetrahydrofuran was added over 45 minutes under an inert atmosphere to amixture of 2 g of magnesium and 15 ml of tetrahydrofuran while thetemperature rose to 56° C. and the reaction was started by addition of1,2-dibromoethane. The mixture was returned to 20° C. and was stirred at20° C. for 45 minutes under an inert atmosphere to obtain a 1.05 Mmagnesium solution.

1.730 g of copper chloride were added with stirring at -20° C. under aninert atmosphere to 38 ml of the said magnesium solution and the mixturewas stirred for 20 minutes. A solution of 5 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol in 50 ml of anhydrous tetrahydrofuran was added to themixture which was then stirred for 24 hours under an inert atmosphere at20° C. and was then poured into 600 ml of iced water containing 60 g ofammonium chloride. The decanted aqueous phase was extracted with diethyloxide containing triethylamine and the combined organic phase was washedwith aqueous saturated sodium chloride solution, dried and evaporated todryness. The residue was chromatographed over silica gel and was elutedwith a 95-5 methylene chloride-acetone mixture to obtain 10.3 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminoethylthio)-phenyl]-17α-(prop-1-ynyl)-Δ⁹ -estrene-5α,17β-diol.

IR Spectrum: Absorption at 3600 cm⁻¹ (OH); at 2240 cm⁻¹ (C.tbd.C); at1705 and 1670 cm⁻¹ (CO and conjugated CO); at 1615 and 1490 cm⁻¹(aromatic bands).

STEP C:11β-[4-(N,N-dimethylaminoethylthio)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one

A mixture of 20.6 ml of 2 N hydrochloric acid, 10.3 g of the product ofStep B and 72 ml of methanol was stirred at 20° C. under an inertatmosphere for 25 minutes and was neutralized by addition of aqueoussaturated sodium bicarbonate solution. 200 ml of diethyl oxide wereadded to the mixture and the decanted aqueous phase was extracted withdiethyl oxide. The combined organic phases were washed with aqueoussaturated sodium chloride solution, dried and evaporated to dryness andthe residue was chromatographed over silica gel. Elution with a 9-1methylene chloride-methanol mixture yielded 3 g of11β-[4-(N,N-dimethylaminoethylthio)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one which after crystallization by empasting withdiisopropyl oxide melted at 145° C. and had a specific rotation of[α]_(D) ²⁰ =+125°±2° (c=1% in chloroform).

EXAMPLE 29 11β-[4-(N,N-dimethylamino)-phenyl]-21-trimethylsilyl-19-nor-17β-Δ⁴,9 -pregnadiene-20-yne-17β-ol-3-one

STEP A:3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-21-trimethylsilyl-19-nor-17α-Δ⁹-pregnene-20-yne-5α,17β-diol

A mixture of 13 ml of a 1.6 M ethyl magnesium bromide in tetrahydrofuranand 13 ml of anhydrous tetrahydrofuran was stirred for 5 minutes at 0°to 5° C. and 3.4 ml of trimethylsilyl acetylene were added theretodropwise. The temperature was allowed to rise to 20° C. and the mixturewas then stirred for 20 minutes. Then, a solution of 1.12 g of theproduct of Step B of Example 7 in 10 ml of anhydrous tetrahydrofuran wasadded dropwise to the mixture and the mixture was stirred at roomtemperature for 16 hours and was poured into aqueous ammonium chloridesolution. The mixture was stirred at room temperature for 10 minutes andwas extracted with methylene chloride. The organic phase was washed withaqueous saturated sodium chloride solution, was dried and evaporated todryness. The residue was chromatographed over silica gel and was elutedwith a 6-4 petroleum ether-ethyl acetate mixture to obtain 680 mg of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-21-trimethylsilyl-19-nor-17α-Δ⁹-pregnene-20-yne-5α,17β -diol with a specific rotation of [α]_(D) ²⁰=-76.5°±3° (c=0.5% in chloroform).

STEP B:11β-[4-(N,N-dimethylamino)-phenyl]-21-trimethylsilyl-19-nor-17α-Δ⁴,9-pregnadiene-20-yne-17β-ol-3-one

A mixture of 1 ml of 2 N hydrochloric acid, 562 mg of the product ofStep A and 15 ml of methanol was stirred at room temperature for 40minutes and was poured into aqueous sodium bicarbonate solution. Themixture was extracted with ether and the organic phase was washed withaqueous saturated sodium chloride solution, was dried and evaporated todryness. The residue was chromatographed over silica gel and was elutedwith a 6-4 petroleum ether-ethyl acetate mixture to obtain 364 mg of11β-[4-(N,N-dimethylamino)-phenyl]-21-trimethylsilyl-19-nor-17α-Δ⁴,9-pregnadiene--20-yne-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰=+97.5°±3° (c=0.35% in CHCl₃).

Analysis: C₃₁ H₄₁ NO₂ Si; molecular weight=487.76 Calculated: %C, 76.33;%H, 8.47; %N, 2.87. Found: %C, 76.4; %H, 8.7; %N, 2.8.

EXAMPLE 30 N-oxide of11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)]-.DELTA.⁴,9-estradiene-17β-ol-3-one

A solution of 0.64 g of m-chloroperbenzoic acid in 12.8 ml of methylenechloride was added over 15 minutes at 0° to 5° C. to a solution of 1.4 gof the product of Example 23 in 28 ml of methylene chloride and themixture was stirred at 0° to 5° C. for one hour and was then poured intoaqueous 0.2 N sodium thiosulfate solution. The decanted aqueous phasewas extracted with methylene chloride and the organic phase was washedwith aqueous sodium bicarbonate solution, dried and evaporated todryness. The residue was chromatographed over silica gel and was elutedwith an 8-2 mixture to obtain 1.28 g of N-oxide of11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one. The product was dissolved in a mixture ofmethylene chloride and diisopropyl oxide and the mixture was vacuumfiltered to obtain 1.075 g of the said product melting at 215° C. andhaving a specific rotation of [α]_(D) ²⁰ =+74.5°±2.5° (c=0.7% in CHCl₃).

EXAMPLE 31 Hemifumarate of11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one

A mixture of 0.378 g of fumaric acid in 4.54 ml of ethanol was added toa mixture of 1.44 g of the product of Example 23 in 2.88 ml of ethanoland the mixture was stirred at 60° C. for 30 minutes. The mixturereturned to 20° C. and was stirred. The mixture was evaporated todryness and the residue was taken up in ether. The mixture was vacuumfiltered and the product was dried to obtain 1.70 g of hemifumarate of11β-[4-(N,N-dimethylaminomethyl)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one melting at 160° C. and having a specificrotation of [α]_(D) ²⁰ =+70.5°±2.5° (c=0.8% in CHCl₃).

EXAMPLE 3211β-[4-(N,N-dipropylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

STEP A: 3,3-[1,2-ethanediyl-bisoxy]-11β-4-(N,N-dipropylamino)-phenyl]-17α-(prop-1-ynyl)-Δ⁹ -estrene-5α,17β-diol

A solution of 52 g of 4-bromo-N,N-dipropyl-aniline in 110 ml oftetrahydrofuran was added dropwise at 40° C. under an inert atmosphereto a mixture of 5 g of magnesium and 15 ml of anhydrous tetrahydrofuranto obtain a 1.1 M magnesium solution. A solution of 5.55 g of3,3-[1,2-ethanediyl-bisoxy]-5α,10α-epoxy-17α-(prop-1-ynyl)-Δ⁹(11)-estrene-17β-ol and 200 mg of cuprous chloride was stirred at 0° to 5°C. and then 50 ml of the magnesium solution were added thereto over 15minutes. The mixture was stirred at 20° C. for one hour and was thenpoured into aqueous saturated ammonium chloride solution. The mixturewas extracted with ether and the organic phase was dried and evaporatedto dryness. The residue was chromatographed over silica gel and waseluted with a 7-3 toluene-ethyl acetate mixture to obtain 6.3 g of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dipropylamino]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α, 17β-diol with a specific rotation of [α]_(D) ²⁰ =-56°±2°(c=0.8% in CHCl₃).

Analysis: C₃₅ H₄₉ NO₄ ; molecular weight =547.75 Calculated: %C, 76.74;%H, 9,02; %N, 2.56. Found: %C, 76.6; %H, 9.2; %N, 2.5.

STEP B: 11β-[4-(N,N-dipropylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one

A mixture of 10 ml of 2 N hydrochloric acid, 5.83 g of the product ofStep A and 80 ml of methanol was stirred at 20° C. for 50 minutes andwas then neutralized by addition of N sodium hydroxide solution. Themixture was evaporated to dryness under reduced pressure and the residuewas taken up in methylene chloride. The organic phase was washed withwater, dried and evaporated to dryness and the residue waschromatographed over silica gel. Elution with a 3-1 toluene-ethylacetate mixture yielded 3.81 g of11β-[4-(N,N-dipropylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one.

IR Spectrum: Absorption at 3600 cm⁻¹ (OH); at 1654 cm⁻¹ (C═O); at1610-1595-1558 and 1517 cm⁻¹ (Δ⁴,9 and aromatic bands); at 2240 cm⁻¹(C.tbd.C).

The following products were prepared by the process of the inventionusing the appropriate starting materials:

(A) 11β-[4-(N-ethyl-N-methylamino)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one melting at 174° C. and having a specificrotation of [α]_(D) ²⁰ =+149°±2.5° (c=1% in CHCl₃).

(B)11β-[N-methyl-2,3-dihydro-1H-indol-5-yl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one melting at 176° C. and having a specificrotation of [α]_(D) ²⁰ =+133°±3° (c=0.8% in CHCl₃).

(C)3-hydroxyimino-11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol (Z isomer) melting at 260° and having a specificrotation of [α]_(D) ²⁰ =+141°±3.5° (c=0.8% in CHCl₃) and thecorresponding E isomer melting at 220° C. and having a specific rotationof [α]_(D) ²⁰ =+164°±3.5° (c=0.8% in CHCl₃).

(D) N-oxide of 11β-[4-pyrrolidyl-phenyl]-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one melting at 220° C. and having a specificrotation of [α]_(D) ²⁰ =+88°±2.5° (c=0.75% in CHCl₃ )

(E)11β-[4-(N-methyl-N-isopropylamino)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰=+140°±3.5° (c=0.5% in CHCl₃).

(F) N-oxide of11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰ =+60.5°(c=1.2% in CHCl₃).

(G) N-oxide of11β-[(N-methyl)-2,3-dihydro-1H-indol-5-yl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one with a specific rotation of [α]_(D) ²⁰=+103°±2.5° (c=0.8% in CHCl₃).

(H)11β-[4-(N-methyl-N-trimethylsilylmethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one.

(I)11β-[4-(N-methyl-N-dimethylaminoethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ⁴,9-estradiene-17β-ol-3-one.

(J)11β-[4-(N-methyl-piperazin-1-yl)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one.

(K) 11β-[4-(N,N-dimethylamino)-phenyl]-17-hydroxyimino-Δ⁴,9-estradiene-3-one with a specific rotation of [α]_(D) ²⁰ =+207.5°±3.5°(c=1% in CHCl₃).

(L) 3(E)-hydroxyimino-11β-[4-(N,N-dimethylamino)-phenyl]-B17-hydroxyimino-Δ⁴,9 -estradiene-3-one with a specific rotation of[α]_(D) ²⁰ =+195°±3° (c=1% in CHCl₃) and its corresponding 3(Z) isomerwith a specific rotation of [α]_(D) ²⁰ =+163°±2.5° (c=0.6% in CHCl₃).

EXAMPLE 33

Tablets were prepared containing 50 mg of the product of Example 4 andsufficient excipient of talc, starch and magnesium stearate for a finaltablet weight of 120 mg.

PHARMACOLOGICAL STUDY

I. Activity of products on hormonal receptors

A. Mineralcorticoidal receptor of kidneys of the rat

Male Sprague-Dawley EOPS rats weighing 140 to 160 g weresurrenalectomized 4 to 8 days previously were killed and their kidneyswere perfused in situ with 50 ml of a buffer (10 mM of Tris 0.25 M ofSaccharose and sufficient hydrochloric acid for a pH of 7.4). Thekidneys were then removed, decapsulated and homogenized at 0° C. with ofa polytetrafluoroethylene-glass Potter (1 g of tissue per 3ml ofbuffer). The homogenate was centrifuged for 10 minutes at 800 g at 0° C.

After elimination of the fixation of tritied aldosterone withglucocorticoid receptor, 21-methyl-Δ¹,4,6 -pregnatriene-20-yne-11β,17β-diol-3-one fixed only with the glucocorticoid receptorwas added to the surnageant at a final concentration of 10⁻⁶ M. Thesurnageant was ultracentrifuged at 105,000 g for 60 minutes at 0° C. andaliquoits of the resulting surnageant were incubated at 0° C. with aconstant concentration (T) of tritied aldosterone in the presence ofincreasing concentrations (0-2500×10⁻⁹ M) of cold aldosterone or thecold test product. After a time (t) of incubation, the concentration oftied tritied aldosterone (B) was measured by the technique of adsorptionon carbon-dextran.

B. Androgen receptor of prostate of rats

Male Sprague-Dawley EOPS rats weighing 160 to 200 g were castrated and24 hours later, the animals were killed. The prostates were removed,weighed and homogenized at 0° C. with a polytetrafluoroethylene-glassPotter with a buffered TS solution (Tris, 10 mM, 0.25 M Saccharose,HCl-pH of 7.4) using 1 g of tissue per 5 ml of TS. The homogenate wasthen ultracentrifuged at 105,000 g after 60 minutes at 0° C. andaliquoits of the resulting surnageant were incubated at 0° C. for 2hours with a constant concentration (T) of product P or17α-methyl-Δ⁴,9,11 -estratriene-17β-ol-3-one in the presence ofincreasing concentrations (0-1,000×10⁻⁹ M) of either cold P, coldtestosterone or the test compound. The concentration of tied tritied P(B) was measured for each incubate by the technique of adsorption oncarbon-dextran.

C. Progestogen receptor of the uterus of rabbits

Immature rabbits weighing about 1 kg received a cutaneous application of25 μg of estradiol and the animals were killed 5 days later. The uteruswere removed, weighed and homogenized at 0° C. with apolytetrafluoroethylene-glass Potter in a buffered TS solution [Tris 10mM, 0.25 M of Saccharose, HCl-pH of 7.4] with 1 g of tissue per 50 ml ofTS. The homogenate was ultracentrifuged at 105,000 g for 90 minutes at0° C. and aliquoits of the resulting surnageant were incubated at 0° C.for a time (t) with a constant concentration (T) of tritied product R or17,21-dimethyl-19-nor-Δ⁴,9 -pregnadiene-3,20-dione in the presence ofincreasing concentrations (0 to 2500×10⁻⁹ M) of either cold R, coldprogesterone or cold test compound. The concentration of tied tritied R(B) was then measured for each incubate by the technique of adsorptionon carbon-dextran.

D. Gluocorticoid receptor of thymus of rats

Male Sprague-Dawley EOPS rats weighing 160 to 200 g weresurrenalectomized and the animals were killed 4 to 8 days later. Thethymus were removed and homogenized at 0° C. in a buffered TS solutionof 10 mM Tris, 0.25 M of Saccharose, 2 mM of dithiothreitol, HCl for apH of 7.4 using a polytetrafluoroethylene-glass Potter at a rate of 1 gof tissue per 10 ml of TS. The homogenate was ultracentrifuged at105,000 g for 90 minutes at 0° C. and aliquoits of the resultingsurnageant were incubated at 0° C. for a time (t) with a constantconcentration (T) of tritied dexamethasone in the presence of anincreasing concentration (0 to 2500×10⁻⁹ M) of either cold dexamethasoneor cold test product. The concentration of tied tritied dexamethasone(B) was measured for each incubate by the adsorption on carbon-dextrantechnique.

E. Estrogen receptor of uterus of mice

Immature female mice 18 to 21 days old were killed and the uterus wereremoved and homogenized at 0° C. with a polytetrafluoroethylene-glassPotter in a buffered TS solution consisting of 10 mM Tris, 0.25 MSaccharose, HCl for a pH of 7.4 at a rate of 1 g of tissue per 25 ml ofTS. The homogenate was then ultracentrifuged at 105,000 g for 90 minutesat 0° C. and aliquoits of the resulting surnageant were incubated at 0°C. for a time (t) with a constant concentration (T) of tritied estradiolin the presence of increasing concentrations (0 to 1000×10⁻⁹ M) ofeither cold estradiol or cold test compound. The concentration of tiedtritied estradiol (B) was measured for each incubate by the technique ofadsorption on carbon-dextran.

The calculation of the relative affinity of concentration (ARL) wasidentical for all of the above receptor tests. One traced the followingtwo curves: the percentage of tied tritied hormone B/T as a function ofthe logarithm of the cold hormone concentration and B/T as a function ofthe logarithm of the concentration of the cold test product. Onedetermined the line of the equation. ##EQU1## B/T max. is the percentageof tied tritied hormone for an incubation of the tritied hormone atconcentration T B/T min. is the percentage of tied tritied hormone foran incubation of the tritied hormone at a concentration (T) in thepresence of a large excess of cold hormone (2500×10⁻⁹ M).

The intersection of the I₅₀ line and the curves permits one to determinethe concentrations of the cold hormone of the reference (CH) and thecold test compound (CX) which inhibit by 50% the tieing of tritiedhormone with the receptor. The relative affinity of tieing (ARL) of thetest product was determined by the equation: ##EQU2## The results arereported in the following Tables.

    __________________________________________________________________________    Pro-                                                                          duct                                                                          of Time of incubation at 0° C.                                         Ex-                                                                              Mineralo              Gluco-                                               am-                                                                              corticoid                                                                            Androgen                                                                             Progestogen                                                                           corticoid                                                                             Estrogen                                     ple                                                                              2H                                                                              4H                                                                              24H                                                                              2H                                                                              4H                                                                              24H                                                                              2H 4H                                                                              24H                                                                              2H                                                                              4H 24H                                                                              2H                                                                              4H                                                                              24H                                      __________________________________________________________________________    4  --                                                                              --                                                                              0  --                                                                              --                                                                              20 74 --                                                                              640                                                                              --                                                                              270                                                                              265                                                                              0 --                                                                              --                                       17 --                                                                              --                                                                              0  --                                                                              --                                                                              68 81 --                                                                              351                                                                              --                                                                              279                                                                              235                                                                              0 --                                                                              --                                       14 --                                                                              --                                                                              -- --                                                                              --                                                                               0 41 --                                                                              250                                                                              --                                                                               46                                                                               94                                                                              0 --                                                                              --                                       8  --                                                                              --                                                                              0  --                                                                              --                                                                              14,7                                                                             81 --                                                                              268                                                                              --                                                                              212                                                                              167                                                                              0 --                                                                              --                                       10 --                                                                              --                                                                              0  --                                                                              --                                                                              32 78 --                                                                              467                                                                              --                                                                              254                                                                              292                                                                              0 --                                                                              --                                       11 --                                                                              --                                                                              0  --                                                                              --                                                                              9,8                                                                              6,3                                                                              --                                                                              8,3                                                                              --                                                                               9  14                                                                              0 --                                                                              --                                       16 --                                                                              --                                                                              1,7                                                                              --                                                                              --                                                                              29 129                                                                              --                                                                              166                                                                              --                                                                              283                                                                              259                                                                              0 --                                                                              --                                       12 --                                                                              --                                                                              0  --                                                                              --                                                                              2,8                                                                              0,6                                                                              --                                                                              0,4                                                                              --                                                                              5,3                                                                              6,2                                                                              0 --                                                                              --                                       6  --                                                                              --                                                                              0,8                                                                              --                                                                              --                                                                              7,3                                                                              10 --                                                                              4,3                                                                              --                                                                              171                                                                              118                                                                              0 --                                                                              --                                       20 --                                                                              --                                                                              -- --                                                                              --                                                                              2,2                                                                              1,1                                                                              --                                                                              2,5                                                                              --                                                                              7,8                                                                               5 0 --                                                                              --                                       22 --                                                                              --                                                                              0,3                                                                              --                                                                              --                                                                               8 175                                                                              --                                                                              843                                                                              --                                                                              178                                                                              221                                                                              0 --                                                                              --                                       29 --                                                                              --                                                                              0  --                                                                              --                                                                              4,6                                                                              15,2                                                                             --                                                                               38                                                                              --                                                                               79                                                                              104                                                                              0 --                                                                              --                                       __________________________________________________________________________

CONCLUSION

The tested compounds and especially those of Examples 4,10,16,17 and 22present a very remarkable affinity for glucocorticoid and progestogenreceptors as well as a slight affinity for androgen receptors. On thecontrary, the products do not have any activity for mineralcorticoid andestrogen receptors. These results lead to the conclusion that theproducts present an agonist or antagonistic activity to glucocorticoids,progestogens and androgens.

II. Anti-inflammatory Activity

The anti-inflammatory activity of the compound of Example 4 wasdetermined by the classical granuloma test by a modification of theMeier et al test [Experientia, Vol. 6 (1950), p. 469] in which normalfemale Wistar rats weighing 100 to 110 g received an implantation of 2pellets of cotton weighing 10 mg each under the thorax skin. Thesubcutaneous treatment which began immediately after the implantationfor 2 days was 2 injections per day. 16 hours after the last injection,the animals were killed and the pellets together with the granulomatissue formed were weighed in the fresh state and after 16 hours at 60°C. The weight of the granuloma was obtained by subtracting the initialweight of the cotton. The thymus was also removed and weighed todetermine the thymolytic activity of the test product.

At a subcutaneous dose of 50 mg/kg, the product of Example 4 did notshow any gluocorticoidal anti-inflammatory activity or thymolyticactivity.

III. Antiglucocorticoidal Activity

The test used was that of Daune et al [Molecular Pharmacology, Vol. 13(1977), p. 948-955] entitled "The relationship between glucocorticoidstructure and effects upon thymocytes" for mice thymocytes. Thethymocytes of surrenalectomized rats were incubated at 37° C. for 3hours in a nutritive medium containing 5×10⁻⁸ M of dexamethasone in thepresence or absence of the test compound at different concentrations.Tritied uridine was added and incubation was continued for one hour. Theincubates were cooled and treated with a 5% trifluoroacetic acidsolution and the mixture was filtered with Whatman GF/A paper. Thefilter was washed 3 times with a 5% trifluoroacetic acid solution andretained radioactivity on the filter was determined. Glucocorticoids andespecially dexamethasone provoked a lessening of incorporation oftritied uridine and the tested compounds, especially those of Examples4,6,8,10,11,14,16,20 and 22, opposed this effect as can be seen from thefollowing Table.

    ______________________________________                                        Product of                                                                             5 · 10.sup.-8 Dexamethasone                                                          % of inhibition of ef-                               Example  + Product tested                                                                              fect of Dexamethasone                                ______________________________________                                         4       10.sup.-8 M     30                                                            10.sup.-7 M     70                                                            10.sup.-6 M     90                                                   14       10.sup.-8 M     18                                                            10.sup.-7 M     57                                                            10.sup.-6 M     *                                                     8       10.sup.-8 M     22                                                            10.sup.-7 M     53                                                            10.sup.-6 M     *                                                    10       10.sup.-8 M     57                                                            10.sup.-7 M     85                                                            10.sup.-6 M     *                                                    11       10.sup.-8 M     14                                                            10.sup.-7 M     34                                                            10.sup.-6 M     75                                                   16       10.sup.-8 M     28                                                            10.sup.-7 M     60                                                            10.sup.-6 M     99                                                    6       10.sup.-8 M      5                                                            10.sup.-7 M     15                                                            10.sup.-6 M     83                                                   20       10.sup.-8 M      4                                                            10.sup.-7 M     21                                                            10.sup.-6 M     50                                                   22       10.sup.-8 M     16                                                            10.sup.-7 M     69                                                            10.sup.-6 M     *                                                    ______________________________________                                         *A dose of 10.sup.-6 M inhibited totally the effect of dexamethasone     

CONCLUSION

The products of the invention used alone do not provoke any effect ofthe glucocorticoid type and the tested products present a veryremarkable antiglucocorticoid activity and are devoid of anyglucocorticoid activity.

Various modifications of the products and methods of the invention maybe made without departing from the spirit or scope thereof and it is tobe understood that the invention is intended to be limited only asdefined in the appended claims.

What we claim is:
 1. A compound selected form the group consisting of19-nor steroids and 19-nor-D-homo-steroids of the formula ##STR99##wherein R₁ is an organic radical of 1 to 18 carbon atoms containing atleast one atom selected from the group consisting of nitrogen,phosphorous and silicon with the atom immediately adjacent to the11-carbon atom being carbon, R₂ is a hydrocarbon of 1 to 8 carbon atoms,X is selected from the group consisting of a pentagonal ring and ahexagonal ring optionally substituted and optionally containing a doublebond, B and C together form a double bond or an epoxy group, the C═Agroup at position 3 is selected from the group consisting of C═O, ketal,##STR100## --C═NOH, --C═NOAlK₃ and ═CH₂, AlK₁, AlK₂ and AlK₃ areselected from the group consisting of alkyl of 1 to 8 carbon atoms andaralkyl of 7 to 15 carbon atoms and their non-toxic, pharmaceuticallyacceptable acid addition salts.
 2. A compound of claim 1 wherein B and Cform a double bond.
 3. A compound of claim 1 or 2 wherein R₂ is methyl.4. A compound of claim 1, 2 or 3 wherein X and the carbons to which itis attached form the ring of the formula ##STR101## wherein R₂ has theabove definition, the dotted line in the 16,17-position is an optionaldouble bond, Y is the group ##STR102## n is 1 or 2, R₅ is selected fromthe group consisting of hydrogen of 1 to 8 carbon atoms, alkenyl andalkynyl of 2 to 8 carbon atoms, aryl of 6 to 14 carbon atoms and aralkylof 7 to 15 carbon atoms, R₆ may be the same as R₅ and may be selectedfrom the same group of members are R₅ or --OH, R₃ and R₄ areindividually selected from the group consisting of hydrogen, --OH,--OAlK₄, --OCOAlK₅, alkenyl and alkynyl of 2 to 8 carbon atoms,##STR103## and --CN wherein AlK₄, AlK₅ and AlK₈ are selected from thegroup consisting of alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15carbon atoms, AlK₆ is selected from the group consisting of optionallysubstituted alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbonatoms and AlK₇ is alkyl of 1 to 8 carbon atoms and R₃ and R₄ form thegroup ##STR104## and Z₁ is selected from the group consisting ofhydrogen, alkyl of 1 to 8 carbon atoms and acyl of an organic carboxylicacid of 1 to 8 carbon atoms and Z₂ is alkyl of 1 to 8 carbon atoms.
 5. Acompound of claim 4 wherein the D ring is saturated, R₅ and R₆ arehydrogen and n is
 1. 6. A compound of claim 1 wherein the C═A group isC═O.
 7. A compound of claim 1 wherein R₁ is a hydrocarbon of 1 to 18carbon atoms containing at least one nitrogen atom.
 8. A compound ofclaim 7 wherein R₁ is a primary, secondary or tertiary alkyl of 1 to 8carbon atoms containing at least one heteroatom of the group consistingof nitrogen, sulfur and oxygen at least one being nitrogen orsubstituted with a heterocycle containing at least one nitrogen atom. 9.A compound of claim 7 wherein R₁ is heterocycle containing at least onenitrogen atom optionally substituted with an alkyl of 1 to 8 carbonatoms.
 10. A compound of claim 7 wherein R₁ is aryl or aralkylcontaining the group ##STR105## wherein R₇ and R₈ are alkyl of 1 to 8carbon atoms or primary, secondary or tertiary alkyl of 1 to 8 carbonatoms containing at least one heteroatom of the group consisting ofnitrogen, sulfur and oxygen of which at least one is nitrogen orsubstituted with a heterocycle containing at least one nitrogen atom.11. A compound of claim 10 wherein R₁ is selected from the groupconsisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, ##STR106##
 12. A compoundof claim 1 wherein R₁ contains an oxidized nitrogen atom.
 13. A compoundof claim 1 selected from the group consisting of11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one,11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one, N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-Δ⁴,9-pregnadiene-20-yne-17β-ol-3-one, N-oxide of9α,10α-epoxy-11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁴-pregnene-20-yne-17β-ol-3-one,11β-[4-(N,N-dimethylamino)phenyl]-17α-(prop-2-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one, N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one and their non-toxic, pharmaceuticallyacceptable acid addition salts.
 14. A process for the preparation of acompound of claim 1 comprising reacting a compound of the formula##STR107## wherein K is a ketone blocked in the form of a ketal,thioketal, oxime or methyloxime and R₁, R₂ and X have the abovedefinitions with a dehydration agent capable of freeing the ketone groupto form a compound of the formula ##STR108## and either reacting thelatter with a ketalization agent to obtain a compound of the formula##STR109## or reacting the compound of formula I_(A) ' with NH₂ OH orNH₂ OAlK₃ wherein AlK₃ has the above definition to obtain a compound ofthe formula ##STR110## wherein R is hydrogen or AlK₃ or reacting acompound of formula I_(A) ' with a reducing agent capable of selectivelyreducing the 3-keto group to obtain a compound of the formula ##STR111##and reacting the latter with an etherification agent capable ofintroducing AlK₁ to obtain a compound of the formula ##STR112## orreacting the compound of formula I_(D) ' with an esterification agentcapable of introducing COAlK₂ to obtain a compound of the formula##STR113## or transforming the compound of formula I_(A) ' by knownmethods to a compound wherein the C═A group is CH₂ -- and optionallyreacting a compound of formula I_(A) ', I_(B) ', I_(C) ', I_(D) ', I_(E)' or I_(F) ' with an acid to form the corresponding acid addition saltor with an oxidation agent to obtain when R₁ is a radical containing anitrogen atom a compound having in the 11β-position a radical whereinthe nitrogen atom is in the oxide form and B and C optionally form anepoxide bridge or when R₁ does not contain a nitrogen atom, a compoundwhere B and C form an epoxide bridge and when the compound contains thenitrogen oxide and the B and C group form an epoxide bridge, selectivelyreducing the oxidized nitrogen atom in R₁ and optionally reacting thelatter with an acid to form the acid addition salt.
 15. A process ofclaim 16 wherein X and the carbons to which it is attached form the ringof the formula ##STR114## wherein R₂ has the above definition, thedotted line in the 16,17-position is an optional double bond, Y is thegroup ##STR115## n is 1 or 2, R₅ is selected from the group consistingof hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl and alkynyl of 2 to 8carbon atoms, aryl of 6 to 14 carbon atoms and aralkyl of 7 to 15 carbonatoms, R₆ may be the same as R₅ and may be selected from the same groupof members as R₅ or --OH, R₃ and R₄ are individually selected from thegroup consisting of hydrogen, --OH, --OAlK₄, --OCOAlK₅, alkenyl andalkynyl of 2 to 8 carbon atoms, ##STR116## and --CN wherein AlK₄, AlK₅and AlK₈ are selected from the group consisting of alkyl of 1 to 8carbon atoms and aralkyl of 7 to 15 carbon atoms, AlK₆ is selected fromthe group consisting of optionally substituted alkyl of 1 to 8 carbonatoms and aralkyl of 7 to 15 carbon atoms and AlK₇ is alkyl of 1 to 8carbons atoms and R₃ and R₄ form the group ##STR117## and Z₁ is selectedfrom the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms andacyl of an organic carboxylic acid of 1 to 8 carbon atoms and Z₂ isalkyl of 1 to 8 carbon atoms.
 16. A process for the preparation of acompound of the formula ##STR118## wherein R₁, R₂ and X have thedefinition of claim 1 and K is selected from the group consisting ofketal, thioketal, oxime and methyloxime wherein a compound of theformula ##STR119## is reacted with a compound selected from the groupconsisting of LiCu (R₁)₂, LiR₁ and R₁ Mg Hal wherein R₁ has the abovedefinition and Hal is a halogen in the presence of a cuprous halide. 17.A process for the preparation of a compound of the formula ##STR120##wherein R₁, R₂ and K have the above definitions, R₃ ' is selected fromthe group consisting of --OH and OR_(c), R_(c) is the residue AlK₄ of anether group or COAlK₅ of an ester group, AlK₄ and AlK₅ having the abovedefinitions, and R₄ ' is hydrogen or alkenyl or alkynyl of 2 to 8 carbonatoms comprising reacting a compound of the formula ##STR121## with acompound selected from the group consisting of LiCu(R₁)₂, R₁ Li and R₁Mg Hal wherein R₁ and Hal have the above definitions in the presence ofa cuprous halide to obtain a compound of the formula ##STR122## andeither reducing the latter to obtain the corresponding 17-ol compound orwith an appropriate magnesium to obtain the corresponding17α-substituted-17β-ol steroid or with an organometallic derivative suchas a lithium or potassium derivative to obtain the corresponding17α-substituted-17β-ol steroid or with a cyanuration agent to obtain thecorresponding 17α-ol-17β-cyano steroid, protecting the hydroxy group andreacting the latter with an organometallic compound as discussed aboveto obtain the corresponding 17α-substituted-17β-ol steroid and in thecase of one of the compounds obtained is 17-hydroxylated, reacting itwith an etherification agent or esterification agent and in the casewhen one of the compounds contains a 17 substituent with a triple bondreacting the latter with a reducing agent to obtain the correspondingethylenic derivative.
 18. A compound selected from the group consistingof ##STR123## wherein R₁, R₂ and X have the definition of claim 1 and Kis selected from the group consisting of ketal, thioketal, oxime andmethyloxime.
 19. A compound of claim 18 selected from the groupconsisting of3,3-[1,2-ethanediyl-bisoxy]-11β-[4-trimethylsilylphenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol,3,3-[1,2-ethanediyl-bisoxy]-11β-(4-pyridyl)-17α-(prop-1-ynyl)-.DELTA.⁹-estrene-5α,17β-diol,3,3-[1,2-ethanediyl-bisoxy]-11β-[3-(N,N-dimethylamino)-propyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol,3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol,3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-Δ⁹-estrene-5α,17β-diol,3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁹-pregnene-20-yne-5α,17β-diol and3,3-[1,2-ethanediyl-bisoxy]-11β-[4-(N,N-dimethylamino)-phenyl]-17.alpha.-(prop-2-ynyl)-Δ⁹-estrene-5α,17β-diol, 3,3-/1,2-ethane dilyl-bisoxy/-5α,10α-epoxy-17α-(prop-1-ynyl)Δ⁹(11) -estrene-17β-ol.
 20. Anantiglucocorticoid composition comprising an antiglucocorticoidallyeffective amount of at least one compound of claim 1 and an inertcarrier.
 21. A composition of claim 20 wherein B and C form a doublebond.
 22. A composition of claim 20 wherein R₂ is methyl.
 23. Acomposition of claim 20 wherein X and the carbons to which it isattached form the ring of the formula ##STR124## wherein R₂ has theabove definition, the dotted line in the 16,17-position is an optionaldouble bond, Y is the group ##STR125## n is 1 or 2, R₅ is selected fromthe group consisting of hydrogen of 1 to 8 carbon atoms, alkenyl andalkynyl of 2 to 8 carbon atoms, aryl of 6 to 14 carbon atoms and aralkylof 7 to 15 carbon atoms, R₆ may be the same as R₅ and may be selectedfrom the same group of members as R₅ or --OH, R₃ and R₄ are individuallyselected from the group consisting of hydrogen, --OH, --OAlK₄,--OCOAlK₅, alkenyl and alkynyl of 2 to 8 carbon atoms, ##STR126## and--CN wherein AlK₄, AlK₅ and AlK₈ are selected from the group consistingof alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbon atoms,AlK₆ is selected from the group consisting of optionally substitutedalkyl of 1 to 8 carbon atoms and aralkyl to 7 to 15 carbon atoms andAlK₇ is alkyl of 1 to 8 carbon atoms and R₃ and R₄ form the group##STR127## and Z₁ is selected from the group consisting of hydrogen,alkyl of 1 to 8 carbon atoms and acyl of an organic carboxylic acid of 1to 8 carbon atoms and Z₂ is alkyl of 1 to 8 carbon atoms.
 24. Acomposition of claim 23 wherein the D ring is saturated, R₅ and R₆ arehydrogen and n is
 1. 25. A composition of claim 20 wherein the C═A groupis C═O.
 26. A composition of claim 20 wherein R₁ is a hydrocarbon of 1to 18 carbon atoms containing at least one nitrogen atom.
 27. Acomposition of claim 26 wherein R₁ is a primary, secondary or tertiaryalkyl of 1 to 8 carbon atoms containing at least one heteroatom of thegroup consisting of nitrogen, sulfur and oxygen at least one beingnitrogen or substituted with a heterocycle containing at least onenitrogen atom.
 28. A composition of claim 26 wherein R₁ is heterocyclecontaining at least one nitrogen atom optionally substituted with analkyl of 1 to 8 carbon atoms.
 29. A composition of claim 26 wherein R₁is aryl or aralkyl containing the group ##STR128## wherein R₇ and R₈ arealkyl of 1 to 8 carbon atoms or primary, secondary or tertiary alkyl of1 to 8 carbon atoms containing at least one heteroatom of the groupconsisting of nitrogen, sulfur and oxygen of which at least one isnitrogen or substituted with a heterocycle containing at least onenitrogen atom.
 30. A composition of claim 29 wherein R₁ is selected fromthe group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, ##STR129## 31.A composition of claim 20 wherein R₁ contains an oxidized nitrogen atom.32. The composition of claim 20 wherein the active compound is selectedfrom the group consisting of11β-[4-(N,N-dimethylaminoethoxy)-phenyl]-17α-(prop-1-ynyl)-.DELTA.⁴,9-estradiene-17β-ol-3-one,11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one, N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-Δ⁴,9-pregnadiene-20-yne-17β-ol-3-one, N-oxide of9α,10α-epoxy-11β-[4-(N,N-dimethylamino)-phenyl]-21-chloro-19-nor-17α-Δ⁴-pregnene-20-yne-17β-ol-3-one,11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-2-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one, N-oxide of11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one and their non-toxic, pharmaceuticallyacceptable acid addition salts.
 33. A method of inducingantiglucocorticoid activity in warm-blooded animals comprisingadministering to warm-blooded animals an antiglucocorticoidallyeffective amount of at least one compound of claim
 1. 34. A method ofclaim 33 wherein B and C form a double bond.
 35. A method of claim 33wherein R₂ is methyl.
 36. A method of claim 33 wherein X and the carbonsto which it is attached form the ring of the formula ##STR130## whereinR₂ has the above definition, the dotted line in the 16,17-position is anoptional double bond, Y is the group ##STR131## n is 1 or 2, R₅ isselected from the group consisting of hydrogen of 1 to 8 carbon atoms,alkenyl and alkynyl of 2 to 8 carbon atoms, aryl of 6 to 14 carbon atomsand aralkyl of 7 to 15 carbon atoms, R₆ may be the same as R₅ and may beselected from the same group of members as R₅ or --OH, R₃ and R₄ areindividually selected from the group consisting of hydrogen, --OH,--OAlK₄, --OCOAlK₅, alkenyl and alkynyl of 2 to 8 carbon atoms,##STR132## and --CN wherein AlK₄, AlK₅ and AlK₈ are selected from thegroup consisting of alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15carbon atoms, AlK₆ is selected from the group consisting of optionallysubstituted alkyl of 1 to 8 carbon atoms and aralkyl of 7 to 15 carbonatoms and AlK₇ is alkyl of 1 to 8 carbon atoms and R₃ and R₄ form thegroup ##STR133## and Z₁ is selected from the group consisting ofhydrogen, alkyl of 1 to 8 carbon atoms and acyl of an organic carboxylicacid of 1 to 8 carbon atoms and Z₂ is alkyl of 1 to 8 carbon atoms. 37.A method of claim 36 wherein the D ring is saturated, R₅ and R₆ arehydrogen and n is
 1. 38. A method of claim 33 wherein the C═A group isC═O.
 39. A method of claim 33 wherein R₁ is a hydrocarbon of 1 to 18carbon atoms containing at least one nitrogen atom.
 40. A method ofclaim 39 wherein R₁ is a primary, secondary or tertiary alkyl of 1 to 8carbon atoms containing at least one heteroatom of the group consistingof nitrogen, sulfur and oxygen at least one being nitrogen orsubstituted with a heterocycle containing at least one nitrogen atom.41. A method of claim 39 wherein R₁ is heterocycle containing at leastone nitrogen atom optionally substituted with an alkyl of 1 to 8 carbonatoms.
 42. A method of claim 39 wherein R₁ is aryl or aralkyl containingthe group ##STR134## wherein R₇ and R₈ are alkyl of 1 to 8 carbon atomsor primary, secondary or tertiary alkyl of 1 to 8 carbon atomscontaining at least one heteroatom of the group consisting of nitrogen,sulfur and oxygen of which at least one is nitrogen, or substituted witha heterocycle containing at least one nitrogen atom.
 43. A method ofclaim 42 wherein R₁ is selected from the group consisting of 2-pyridyl,3-pyridyl, 4-pyridyl, ##STR135##
 44. A method of claim 33 wherein R₁contains an oxidized nitrogen atom.
 45. A compound of claim 1 selectedfrom the group consisting of11β-[4-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one and its non-toxic, pharmaceutically-acceptableacid addition salts.
 46. A method of claim 33 wherein the compound isselected from the group consisting of11β-[4,-(N,N-dimethylamino)-phenyl]-17α-(prop-1-ynyl)-Δ.sup.4,9-estradiene-17β-ol-3-one and its non-toxic, pharmaceutically acceptableacid addition salts.